Cause Of Intrahepatic Cholestasis Research Articles

Is primary biliary cholangitis still a challenge? Experience of Hassan II University Hospital FES Morocco

Introduction: Primary biliary cholangitis is a chronic autoimmune hepatopathy and the leading cause of intrahepatic cholestasis. Treatment is mainly based on ursodesoxycholic acid. The aim of our work is to study the epidemiological, clinical and evolutionary profile of PBC, and to determine the factors predictive of a poor response to UDCA in our context. Materials and methods: This is a retrospective descriptive and analytical study of all cases of PBC followed in our training program from June 2012 to February 2023. Results: We recorded all clinical, diagnostic, therapeutic and evolutionary aspects of 70 cases of PBC. Ninety-two percent ( n= 65) were women. The mean age was 57.3 [24-83] years. The circumstances of discovery were dominated by pruritus, and jaundice. M2-type anti-mitochondrial antibodies were positive in 91.4% of cases. 52.14% of cases had associated autoimmune diseases. Treatment was based on UDCA in all cases, combined with corticosteroids and immunosuppressants for patients with overlap syndrome. A biochemical response after one year of treatment according to Paris II criteria was found in 62.85% (44 cases). In univariate analysis, the factors associated with poor response to treatment were : Discovery of cirrhosis at diagnosis , Decompensated cirrhosis , presence of overlap syndrome , poor compliance with UDCA due to non-availability of medication , initial bilirubin level above 30 mg/l , hypoalbuminemia below 35 g/l. Conclusion: Our study shows the frequency of cirrhosis in PBC, which may explain the low response rate to UDCA, a drug that remains difficult to obtain in our Moroccan context, making prognosis poor and management difficult.

Primary Biliary Cholangitis and Rheumatoid Arthritis: An Emerging Association

Primary Biliary Cholangitis (PBC), formerly known as primary biliary cirrhosis, is an autoimmune-related cholestatic hepatopathy, representing a common cause of intrahepatic cholestasis due to progressive bile duct destruction. Often, PBC is linked with other autoimmune disorders such as Sjogren’s syndrome, thyroid dysfunction, scleroderma, and systemic lupus erythematosus. However, the association of PBC with rheumatoid arthritis (RA) is rare, estimated at 1.8 to 5.6%. We present a clinical case of PBC discovered in a patient with deforming rheumatoid arthritis.

An Insight Into Neonatal Cholestasis; A Tertiary Care Hospital Experience in Rawalpindi, Pakistan

Objective: To determine the frequencies of various etiologies of neonatal cholestasis diagnosed by clinical findings and laboratory investigations at the Pak Emirates Military Hospital, Rawalpindi, Pakistan. Study Design: Cross-sectional study. Place and Duration of Study: Pediatric Department of Pak Emirates Military Hospital, Rawalpindi Pakistan, from Jan 2021 to Apr 2022. Methodology: Infants of either gender aged 14 days to six months admitted to Inpatient facility who had jaundice with direct bilirubin and more than 20% of total bilirubin were included in the study. The proforma was formulated to record the clinical features, laboratory investigations, weight, level of activity and consanguinity among the parents. Results: A total of 146 infants were included in the study. Jaundice was seen in 100% of infants, hepatomegaly in 66.4%, splenomegaly in 38.4%, followed by ascites in 25%. The most common aetiology of neonatal cholestasis was Biliary Atresia 26.7% in the extrahepatic Group, Idiopathic Neonatal Hepatitis 25.3% in the intrahepatic Group. Consanguinity was present in parents of 65% of infants. Conclusion: The most common aetiology of extrahepatic Neonatal Cholestasis was Biliary Atresia, while Idiopathic Neonatal Hepatitis and Progressive Familial Intrahepatic Cholestasis were the most common causes of intrahepatic cholestasis.

A novel model based on immune-related genes for differentiating biliary atresia from other cholestatic diseases

Based on a public gene expression database, this study established the immune-related genetic model that distinguished BA from other cholestasis diseases (DC) for the first time. We explored the molecular mechanism of BA based on the gene model. The BA microarray dataset GSE46960, containing BA, other cause of intrahepatic cholestasis than biliary atresia and normal liver gene expression data, was downloaded from the Gene Expression Omnibus (GEO) database. We performed a comprehensive bioinformatics analysis to establish and validate an immune-related gene model and subsequently identified hub genes as biomarkers associated with the molecular mechanisms of BA. To assess the model's performance for separating BA from other cholestasis diseases, we used receiver operating characteristic (ROC) curves and the area under the curve (AUC) of the ROC. Independent datasets GSE69948 and GSE122340 were used for the validation process. The model was built using eight immune-related genes, including EDN1, HAMP, SAA1, SPP1, ANKRD1, MMP7, TACSTD2, and UCA1. In the GSE46960 and validation group, it presented excellent results, and the prediction accuracy of BA in comparison to other cholestasis diseases was good. Functional enrichment analysis revealed significant immunological differences between BA and other cholestatic diseases. Finally, we found that the TNFα-NF-κB pathway is associated with EDN1 gene expression and may explain fibrosis progression, which may become a new therapeutic target. In summary, we have successfully constructed an immune-related gene model that can distinguish BA from other cholestatic diseases, while identifying the hub gene. Our exploration of immune genes provides new clues for the early diagnosis, molecular mechanism, and clinical treatment of biliary atresia.

The Bioinformatic Study Uncovers Probable Critical Genes Involved in the Pathophysiology of Biliary Atresia.

Background Biliary atresia (BA) is an uncommon illness that causes the bile ducts outside and within the liver to become clogged in babies. If left untreated, the cholestasis causes increasing conjugated hyperbilirubinemia, cirrhosis, and hepatic failure. BA has a complicated aetiology, and the mechanisms that drive its development are unknown. The objective of this study was to show the role of probable critical genes involved in the pathophysiology of biliary atresia. Methods We utilised the public Gene Expression Omnibus (GEO) microarray expression profiling dataset GSE46960 to find differentially expressed genes (DEGs) in 64 biliary atresia newborns, 14 infants with various causes of intrahepatic cholestasis, and 7 deceased-donor children as control subjects in our study. The relevant information was looked into. The important modules were identified after functional enrichment, GO and KEGG pathway analyses, protein-protein interaction (PPI) network analyses, and GSEA analysis. Results The differential expression analysis revealed a total of 22 elevated genes. To further understand the biological activities of the DEGs, we run functional enrichment analyses on them. Meanwhile, KEGG analysis has revealed significant enrichment of pathways involved in activating cross-talking with inflammation and fibrosis in BA. SERPINE1, THBS1, CCL2, MMP7, CXCL8, EPCAM, VCAN, ITGA2, AREG, and HAS2, which may play a significant regulatory role in the pathogenesis of BA, were identified by PPI studies. Conclusion Our findings suggested 10 hub genes and probable mechanisms of BA in the current study through bioinformatic analysis.

Etiology and outcome of neonatal cholestasis: an experience in a tertiary center of Bangladesh

BackgroundNeonatal cholestasis (NC) is a major cause of morbidity and mortality in young infants. This study examines the etiology of NC and its outcome during 2 years of follow-up at a tertiary referral center in Bangladesh.ResultsOut of 80 cholestatic infants, 60% had intrahepatic cholestasis with a mean age of onset of 12.4±2.8 days and a mean age of admission of 82.4±29.0 days. The remaining 40% were extrahepatic with a mean age of onset of 6.7±2.3 days and a mean age of admission of 94.6±50.4 days. Biliary atresia (BA), idiopathic neonatal hepatitis (INH), and TORCH (Toxoplasma, rubella, cytomegalovirus, and herpes simplex) infection except rubella were the most common causes. After receiving treatment, 46.2% of the cases improved, 23.8% deteriorated with morbidity, and 30% died. The majority of the children with INH, TORCH, choledochal cyst, hypothyroidism, galactosemia, and urinary tract infection (UTI) with sepsis were improved. Significant mortality was found in BA (56.6%), intrahepatic bile duct paucity (PIBD) (100%), and progressive familial intrahepatic cholestasis (PFIC) (100%) whereas the rest of BA (43.4%) live with persistent morbidity. Significant clinical improvement was observed in 37 (46.2%) cases of cholestasis evidenced by decreasing jaundice, change of color of urine from dark to normal color, change of stool color from pale to yellow, and gradual decrease in liver size from hepatomegaly state. In addition, decreasing median total bilirubin, direct bilirubin, alanine transaminase, gamma-glutamyl transferase, and alkaline phosphatase showed biochemical improvement at 2 years follow-up. The age of admission, etiology, and presence of ascites are the predictors of outcomes.ConclusionBA was the most common cause of extrahepatic while INH and TORCH infection were the most common cause of intrahepatic cholestasis. Majority of children with intrahepatic cholestasis improved but deteriorated with BA and genetic causes. Prompt referral and early diagnosis as well as the etiology of NC were the main determinants of the favorable outcome.

Primary Biliary Cholangitis: Predictors of Poor Response to Ursodeoxycholic Acid after 1 Year of Treatment in Moroccan Patients

Introduction: Primary biliary cholangitis (PBC), the new dominance of primary biliary cirrhosis, is a cholestatic disease of autoimmune etiology and represents the leading cause of intra-hepatic cholestasis. Treatment is mainly based on ursodeoxycholic acid. The biological response to treatment is the main predictor of survival without liver transplantation. The Globe-score has been recently validated as the main prognostic factor. Materials and methods: This is a retrospective study carried out in our department collating all cases of PBC followed in consultation. The aim of our work is to research the predictors of poor response to UDCA. Results: 46 patients were collected. The mean age of the patients was 58.82 years, with a predominance of women (n = 43, 93.5%). 34.78% of patients were in the stage of cirrhosis. Anti-M2 mitochondria antibodies were positive in 44 patients (95.65%). An overlap syndrome was found in 11 patients (23.9%). Treatment was based on UDCA combined with corticosteroid therapy and immunosuppressant for overlap syndrome. A biochemical response at 1 year of treatment according to the Paris II criteria was found in 47.8%. The average value of the globe score was 1.35. A score greater than 0.30 was objectified in 20 cases (43.47%). Nineteen cirrhotic patients (41.30%) had a globe score> 0.30. Factors associated with poor response to therapy were: stage of decompensated cirrhosis, elevated pre-therapy total bilirubin greater than 30 g / l and hypoalbunemia less than 35 g / l. The study of the correlation between Globe score and Paris II showed a strong and significant association with a correlation coefficient estimated at 67%. The Paris II score was significantly correlated with the response to treatment (p = 0.001). Conclusion: In accordance with the data in the literature, the globe-score and Paris II are two similar predictive means for evaluating the response at 1 year of treatment in Moroccan context. Keywords: Morocco, Predictors of response, Primary biliary cholangitis, Ursodeoxycholic acid

Cholestasis syndrome in a comorbid patient: diagnostic difficulties

The purpose of the review article is to demonstrate generalized ideas on the classification and diagnosis of cholestasis syndrome of various etiologies, to consider the possibility of using laboratory and instrumental research methods in real clinical practice in a comorbid patient. The main provisions. According to the mechanism of development, cholestasis is conditionally divided into intrahepatic and extrahepatic, as well as a mixed type. Extrahepatic cholestasis develops with mechanical obstruction of the main extrahepatic or main intrahepatic ducts. Intrahepatic cholestasis as a result of a number of diseases, such as acute viral hepatitis, primary biliary cholangitis, drug damage to the liver, amyloidosis of the liver. In real clinical practice, a combination of several etiological factors leading to the development of cholestasis is possible in a comorbid patient. A clinical observation is given when, in a patient with gallstone disease, melanoma and ulcerative colitis, after excluding a number of possible causes of cholestasis, autoimmune cross syndrome, autoimmune hepatitis and primary sclerosing cholangitis (PSC), was diagnosed, which allowed the initiation of immunosuppressive therapy with 48 mg corticosteroid (per day) and the preparation of ursodeoxycholic acid (UDCA) exhol at a dose of 1500 mg per day. Regardless of the cause of intrahepatic cholestasis, UDCA remains the drug for the treatment of first-line cholestatic lesions. Conclusion. Only a consistent methodological approach, taking into account all the possible causes of cholestasis, can lead to a correct diagnosis and timely adequate treatment in each case.

Alagille syndrome: an uncommon cause of intrahepatic cholestasis in adults

Alagille syndrome (ALGS) is an autosomal-dominant multisystem disorder caused by mutations in Jagged 1 (JAG1) or NOTCH2. The penetrance is low but highly variable. It is almost exclusively diagnosed in children with cholestasis and, more rarely, in their adult relatives. Here, we report the case of a patient diagnosed with ALGS in adulthood. The patient was a 28-year-old male who presented with characteristic facial features, an eye abnormality, chronic cholestasis with bile duct paucity on liver biopsy, atrial defects and stenosis of the left internal carotid artery. A novel frameshift mutation, c.2087_2088insAAAAATGG (p. W697Kfs*49), in JAG1 was identified. To our knowledge, this is the first case of ALGS diagnosed in adulthood in China. ALGS should be considered as a differential diagnosis for intrahepatic cholestasis in adult patients with a wide variety of clinical manifestations, including cardiac disease, skeletal abnormalities, ocular abnormalities and characteristic facial features.

Total Bile Acid Concentration in Duodenal Fluid Is a Useful Preoperative Screening Marker to Rule Out Biliary Atresia.

Duodenal tube test (DTT) is used as a preoperative screening to rule out biliary atresia (BA). In previous reports, DTT was assessed by the color of the duodenal fluid, but there were no quantitative criteria. The aim of this study was to examine the efficacy of DTT based on the total bile acid (TBA) concentration in duodenal fluid. This is a single-center retrospective study of infants with cholestasis who underwent DTT from 2008 to 2016 at the Osaka University Hospital. The cut-off values of maximum TBA in duodenal fluid (dTBA), dTBA/serum TBA ratio (sTBA), and dTBA/serum gamma-glutamyl transpeptidase (sGGT) ratio were assessed for the accuracy in excluding BA. A total of 37 infants were included in this study; 16 infants with BA and 21 infants with other causes of intrahepatic cholestasis. dTBA demonstrated sensitivity of 100% and specificity of 90.5% with the cut-off value of 16.8 μmol/L. Specificity was further improved to 95.2% with dTBA/sTBA ratio (cut-off value: 0.088) and 100% with dTBA/sGGT ratio (cut-off value: 0.076 μmol/U). DTT could be performed 0.8 ± 1.4 days after admission. Hypoglycemia was developed in 1 infant. DTT evaluated by dTBA, dTBA/sTBA ratio, and dTBA/sGGT ratio had high accuracy to rule out BA and could avoid unnecessary surgery in some infants.

Cholestase néonatale

“Cholestasis” means abnormal synthesis or secretion of bile. The main symptom in a neonate or infant is jaundice. Urine is dark, staining diapers, and stools are variably pale or white. Vitamin K should be injected (to prevent coagulation disorders due to malabsorption). The two diagnoses requiring urgent treatment are urinary tract infection and biliary atresia. If stools are permanently white, biliary atresia is highly probable. A few genetic causes of intrahepatic cholestasis should be screened and corrective surgery organized. The diseases responsible for cholestasis in this age group are described as well as the investigations and treatments, including the management of non-specific complications of cholestasis. A delay in the diagnosis of biliary atresia can have such severe consequences that consultation with a hepatology unit or transfer should be easy and rapid.

PO-0592 Distinguishing Congenital Combined Pituitary Hormone Deficiency From Biliary Atresia As A Cause Of Cholestasis In Infants

<h3>Background and aims</h3> Neonatal cholestasis is caused by either biliary atresia or intrahepatic cholestasis. Congenital combined pituitary hormone deficiency (CPHD) is a rare disease and a recognised cause of intrahepatic cholestasis. It is important to differentiate cholestasis due to this entity from cholestasis due to biliary atresia, since both diseases can cause jaundice at about 1 month of age. However, doing so in a timely fashion remains a diagnostic dilemma. This retrospective study was performed to clarify differences between cholestasis due to congenital CPHD and cholestasis due to biliary atresia. <h3>Methods</h3> From 2004 to 2010, 4 infants (2 boys and 2 girls) with cholestasis due to congenital CPHD were admitted to Nagoya City University Hospital. Head magnetic resonance imaging of the 4 infants revealed an invisible pituitary stalk; 3 of these 4 infants had an ectopic posterior pituitary. Liver biopsy was performed in 3 of the 4 infants, and histological findings included giant cell hepatitis. Findings from these 4 infants were then compared with those from55 infants treated in our hospital for cholestasis due to biliary atresia. <h3>Results</h3> The results showed a significant difference in mean gamma-glutamyl transpeptidase levels between the two groups of infants (115.0 IU/l vs. 553.0 IU/l, respectively). <h3>Conclusions</h3> The gamma-glutamyl transpeptidase level was found to be useful for distinguishing congenital CPHD from biliary atresia as the cause of cholestasis. The diagnosis of hypopituitarism should always be considered in infants with unexplained neonatal hepatitis.

′Graves′ disease: A rare cause of cholestasıs

Rarely, intrahepatic cholestasis may occur during the course of Graves' disease. It is important to rule out other causes of intrahepatic cholestasis for diagnosis. In this article, we present a case of intrahepatic cholestasis due to Graves' disease in a 52-year-old male patient with jaundice, pruritus, and weight loss.

Conjugated Hyperbilirubinemia in Children

A variety of anatomic, infectious, autoimmune, and metabolic diseases can lead to conjugated hyperbilirubinemia, both in the newborn period and later in childhood. The pediatric practitioner is most likely to encounter conjugated hyperbilirubinemia in the neonatal period.It is crucial to maintain a high degree of suspicion for cholestasis in the persistently jaundiced newborn. The goal is recognition of conjugated hyperbilirubinemia between 2 and 4 weeks after birth, allowing for the prompt identification and management of infants who have biliary atresia, which remains the most common cause of neonatal cholestasis.

Protocolo diagnóstico de la colestasis

Cholestasis is a very common clinical problem that may occur in all kind of patients. Its varied etiology requires the establishment of clear guidelines to reach an effective diagnosis.The first step should be to determine if cholestasis is due to intra or extrahepatic causes. In order to do so, after conducting a thorough medical history and physical examination with special attention to the right upper quadrant, we must evaluate the bile duct by abdominal ultrasound. Dilatation of the bile duct will point to extrahepatic causes, while its abscence will make us think of intrahepatic cholestasis.In extrahepatic cholestasis additional imaging tests will identify the cause of the obstruction. In case of suspected gallstones, ERCP is the gold standard, allowing therapeutic if needed. In case of suspicion of malignancy, the CT scan can help rule out neoplasias that produce painless jaundice or metastatic lymph nodes compressing the bile duct.The list of causes of intrahepatic cholestasis is extensive, however the performance of several laboratory tests (serology hepatotropic virus, anti-mitochondrial antibodies), a detailed history (consumption of hepatotoxic or full parenteral nutrition, family history of cholestasis, pregnancy) and if necessary cholangiography (PEC intrahepatic) will lead us to a diagnosis in most cases.

Predictive Value of Assessment of Different Modalities in the Diagnosis of Infantile Cholestasis

This study investigated the relative accuracy and roles of abdominal ultrasonography, hepatobiliary scintigraphy and liver biopsy in the diagnosis of infantile cholestasis. A total of 50 infants (27 females) aged 1 - 12 months were classified into those with intrahepatic causes of cholestasis (n = 22) and those with extrahepatic causes (n = 28). Cholestasis is caused by a wide range of conditions and diagnosis requires meticulous history taking, thorough clinical examination and many laboratory tests. The most common cause of intrahepatic cholestasis was found to be idiopathic neonatal hepatitis (54.5%), followed by infectious hepatitis (9.1%), metabolic liver diseases (9.1%), intrahepatic biliary atresia (9.1%) and Alagille syndrome (4.5%). The most common cause of extrahepatic cholestasis was extrahepatic biliary atresia (96.4%). The incidence of choledochal cyst was low (3.6%). The cornerstone of the diagnosis of infantile cholestasis was found to be liver biopsy, which was associated with a high degree of accuracy.

Reloading Against Rare Liver Diseases

Reloading Against Rare Liver Diseases

Sepsis as a cause of intrahepatic cholestasis

The causes of intrahepatic cholestasis include cholestatic viral hepatitis, primary biliary cirrhosis, benign recurrent cholestasis, primary sclerosing cholangitis and sepsis. During sepsis, proinflammatory cytokines and nitric oxide cause cholestasis by impairing hepatocellular and ductal bile formation. We report a 48-year-old woman who was admitted to hospital due to malaise, jaundice, fever and pain in the neck. Physical examination revealed jaundice, tachycardia (pulse rate was 120/min), hypotension 90/60 mm Hg. Laboratory findings showed normocytic normochromic anaemia, inflammatory syndrome and abnormal liver function tests indicating cholestasis and hepatocellular necrosis. Abdominal ultrasonography detected hepatosplenomegaly. Chest computed tomography showed bronchopneumonic infiltrates. Percutaneous liver biopsy was performed using a Menghini needle of 1.4 mm. Pathohystological analysis of the liver tissue confirmed reactive, intrahepatic cholestasis. Blood cultures isolated Staphylococcus aureus. After the diagnosis was established the treatment with broad-spectrum antibiotics was carried out, resulting in the improvement of general condition of the patient, regression of inflammatory syndrome, disappearance of cholestasis and regression of pulmonary infiltrates. Abdominal ultrasonography after antibiotic treatment did not show hepatosplenomegaly. Concerning patients with cholestasis of uncertain origin, we should always think of sepsis as a possible cause in order to start antibiotic treatment in time.

La cholestase intrahépatique gravidique

Intrahepatic cholestasis of pregnancy is the most common liver disorder unique to pregnancy in women without hypertension. The cause of intrahepatic cholestasis of pregnancy is still under discussion but genetic and hormonal factors are predominant. The main symptom is skin pruritus, associated with increase in serum transaminase activities and bile acid concentrations. Intrahepatic cholestasis of pregnancy carries a risk for the pregnancy because of preterm delivery and sudden intrauterine fetal death. Ursodeoxycholic acid (usually 1000mg per day or 15mg/kg per day) is currently the most effective pharmacologic treatment. Ursodeoxycholic acid reduces pruritus, transaminases and bile acid levels and probably prematurity without adverse effects. Obstetric management is still under debate. The majority of authors recommend active management with elective delivery usually before or at 38 weeks of gestation according the severity of cholestasis. Prospective controlled studies are required to confirm the benefit of ursodeoxycholic acid treatment on fetal outcome and to clarify the obstetrical management near term.

Cholestatic Jaundice as a Paraneoplastic Presentation of Hodgkinʼs Lymphoma

Purpose: A 21 year old female was transferred to our hospital for the management of hyperbilirubinemia in the setting of a recent diagnosis of Hodgkin's disease. Upon initial assessment, laboratory workup revealed cholestasis with elevated transaminases, alkaline phosphatase, and no coagulopathy. The rest of the workup was negative. Abdominal imaging was negative. Her bilirubin continued to rise, and a liver biopsy showed pericentral cholestasis and mild non-specific lobular inflammation. She was started on prednisone with a gradual taper. Six weeks into treatment, her jaundice resolved. Hodgkin's disease-related cholestasis has multiple pathophysiologic mechanisms. The differential diagnosis of jaundice in a lymphoma patient includes the more common etiologies of sepsis, drugs, viral infections and hepatic metastasis. These diagnoses can usually be ruled out with an extensive initial workup. However, liver involvement in Hodgkin's disease (HD) can be a more subtle finding that requires a prompt and a more invasive workup. The three main causes of intrahepatic cholestasis in association with lymphomas are hepatic lymphoma, vanishing bile duct syndrome (VBDS) and a paraneoplastic phenomenon. Secondary hepatic lymphoma is almost always an end-stage manifestation of the disease that can rapidly progress into fulminant hepatic failure. Primary hepatic lymphoma, on the other hand, occurs in the absence of extrahepatic disease. It has an extremely dismal prognosis. VBDS is another cause of cholestasis that has been associated with HD. Histologically, this entity is characterized by the absence of bile ducts in the portal triads. Treatment with steroids, ursodeoxycolic acid and IVIG has been described with not enough evidence to advocate the use of either therapy. The last mechanism is due to a paraneoplastic effect. Stauffer described a syndrome of nonmetastatic nephrogenic hepatic dysfunction in association with renal cell carcinoma. Later on a similar paraneoplastic cholestatic entity has been described in association with multiple malignancies including lymphoma. The proposed mechanism for this rare entity could be overexpression of IL-6 by the tumor cells, and hence the reported literature on the improvement of the cholestasis after treating the malignancy. Conclusion: In conclusion, the possibility of hepatic lymphoma, VBDS or a paraneoplastic mechanism should be considered in every case of jaundice and HD. This can be a life threatening complication that can progress to fulminant hepatic failure short of early and appropriate intervention.