Cause Of Intrahepatic Cholestasis Research Articles

50 Years Ago in The Journal of Pediatrics: Neonatal hepatitis in siblings

Peterman MG. J Pediatr 1957;50:315-20 In 1957, M. G. Peterman reported two sets of siblings presenting in the neonatal period with cholestasis. With the limited available therapy, there was progression of disease leading to death. Common to all the cases was the presence of giant cell transformation of liver cells on post-mortem examination resulting in the diagnosis of neonatal hepatitis. Peterman described the diagnosis as a “general all-inclusive term, probably as satisfactory as any,” recognizing that the etiology was ill-defined. Over the last 50 years, cases of familial neonatal cholestasis have served as models to elucidate hepatic physiology, to identify specific genetic and molecular defects, and to expand the differential diagnosis of intrahepatic cholestasis presenting in the newborn period. This, in turn, has lead to improved diagnostic and therapeutic modalities. Many of the known genetic forms of intrahepatic cholestasis fall into broad categories of defects in embryogenesis, bile acid metabolism, and canalicular transport. Other causes of intrahepatic cholestasis include multi-organ disorders, metabolic diseases, and other clinically definable syndromes.1Balistreri W.F. Bezerra J.A. Whatever happened to “neonatal hepatitis”?.Clinics in Liver Disease. 2006; 10: 27-33Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Evaluation of infants presenting with conjugated hyperbilirubinemia has evolved to include recognition of the immature physiology of the newborn liver, evaluation for infection and metabolic disease, radiographic study of the biliary anatomy, and differentiation of intrahepatic cholestatic syndromes through a combination of clinical features, serum bile acid level, serum gamma glutamyl transpeptidase level, and liver biopsy. Diagnostic studies of the future include development of a gene chip, biomarkers of genetic defects, and targeted testing of molecular defects. Continued understanding of liver physiology and molecular pathophysiology of cholestatic disease has resulted in therapy to reduce symptoms, improve nutritional status, and delay progression of disease. These measures encompass medical therapy as well as surgical intervention including liver transplantation. The goal, however, should be to avoid the need for liver transplantation by defining and treating the underlying disease. Despite the progress over the last 50 years in diagnosis and treatment of neonatal hepatitis, approximately 15% of patients continue to be diagnosed with idiopathic disease.1Balistreri W.F. Bezerra J.A. Whatever happened to “neonatal hepatitis”?.Clinics in Liver Disease. 2006; 10: 27-33Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Clearer definition of phenotype, precise nomenclature of known diseases, and multi-center registries will be critical in improving diagnostic and treatment strategies in those with defined disease and in understanding the etiology of disease in those yet undiagnosed cases.

Unusual causes of intrahepatic cholestatic liver disease

We report five cases with unusual causes of intrahepatic cholestasis, including consumption of Teucrium polium (family Lamiaceae) in the form of tea, Stauffer's syndrome, treatment with tamoxifen citrate for breast cancer, infection with Coxiella Burnetii (acute Q fever), and infection with Brucella melitensis (acute brucellosis).

Cholestase met een normaal γ-gt: wat nu?

Four infants are presented with a genetic cause of intrahepatic cholestasis: progressive familiar intrahepatic cholestasis. This disorder belongs to a group of autosomal recessive disorders with hepatocellular cholestasis during infancy and a low serum γ-gt. In case of cholestasis of a young child with low serum γ-gt and normal anatomical biliary system, pfic type 1 and 2 should be considered, especially when infectious and metabolic diseases are excluded. pfic type 3 shows elevated levels of γ-gt. All described patients suffered from pfic type 2. The first patient presented with cerebral insufficiency due to intraventricular hematomas, twin sisters presented with failure to thrive and the last patient with persistent cholestatic icterus. The treatment which mainly consists of surgical treatment will be discussed.

IFC(editors sections)

We report a case of ticlopidine-induced cholestasis in a 62-year-old man with no previous hepatobiliary disease, who presented with jaundice and pruritus 4 weeks after starting ticlopidine therapy. Other drugs taken by the patient were not considered probable causes. The diagnostic evaluation showed no biliary obstruction and other possible causes of intra-hepatic cholestasis were excluded. The liver biopsy showed a cholestatic hepatitis with centrolobular steatosis and aggression of interlobular bile ducts. Steroid therapy was started but it was discontinued for reactivation of cytomegalovirus (CMV) infection that needed anti-viral therapy for 15 days. The disease ran a severe and protracted course, with anicteric cholestasis elevated 17 months after drug withdrawal. No rechallenge was attempted and ticlopidine was replaced with another anti-platelet drug.Cholestatic hepatitis has been reported infrequently in relation to several drugs, mainly chlorpromazine, and only once with ticlopidine. Its pathogenesis is still unknown, although some clinical findings and experimental results suggest that the drug may act through a toxic mechanism.

Ticlopidine-induced cholestatic hepatitis successfully treated with corticosteroids: a case report

Abstract We report a case of ticlopidine-induced cholestasis in a 62-year-old man with no previous hepatobiliary disease, who presented with jaundice and pruritus 4 weeks after starting ticlopidine therapy. Other drugs taken by the patient were not considered probable causes. The diagnostic evaluation showed no biliary obstruction and other possible causes of intra-hepatic cholestasis were excluded. The liver biopsy showed a cholestatic hepatitis with centrolobular steatosis and aggression of interlobular bile ducts. Steroid therapy was started but it was discontinued for reactivation of cytomegalovirus (CMV) infection that needed anti-viral therapy for 15 days. The disease ran a severe and protracted course, with anicteric cholestasis elevated 17 months after drug withdrawal. No rechallenge was attempted and ticlopidine was replaced with another anti-platelet drug. Cholestatic hepatitis has been reported infrequently in relation to several drugs, mainly chlorpromazine, and only once with ticlopidine. Its pathogenesis is still unknown, although some clinical findings and experimental results suggest that the drug may act through a toxic mechanism.

Intrahepatic cholestasis after liver transplantation

Cholestasis is a common sequela of liver transplantation. Although the majority of cases remain subclinical, severe cholestasis may be associated with irreversible liver damage, requiring retransplantation. Therefore, it is essential that clinicians be able to identify and treat the syndromes associated with cholestasis. In this review, we consider causes of intrahepatic cholestasis. These may be categorized by time of occurrence, namely, within 6 months of liver transplantation (early) and thereafter (late), although there may be an overlap in their causes. The causes of intrahepatic cholestasis include ischemia/reperfusion injury, bacterial infection, acute cellular rejection, cytomegalovirus infection, small-for-size graft, drugs for hepatotoxicity, intrahepatic biliary strictures, chronic rejection, hepatic artery thrombosis, ABO blood group incompatibility, and recurrent disease. The mechanisms of cholestasis in each category and the clinical presentation, diagnosis, treatment, and outcome are discussed in detail. (Liver Transpl 2003;9:1005-1018.)

Severe intrahepatic cholestasis caused by amiodarone toxicity after withdrawal of the drug: a case report and review of the literature.

Cholestasis has been reported as a rare presentation among patients with severe liver injury secondary to amiodarone hepatic toxicity. We report an unusual case of amiodarone-induced cholestatic hepatotoxicity occurring after amiodarone had been discontinued and the initial abnormal liver function findings had improved. The patient, without jaundice at the initial presentation, developed severe jaundice about 4 months after withdrawal of amiodarone. Light and transmission electron microscopic examination of a specimen secured by computed tomographically guided liver biopsy was consistent with amiodarone hepatic toxicity as the cause of intrahepatic cholestasis. An abdominal ultrasound, endoscopic retrograde cholangiography, and dimethyl iminodiacetic acid and computed tomographic scans of the abdomen all failed to demonstrate any other causes for jaundice other than amiodarone toxicity. Thus, amiodarone hepatic toxicity may occur after drug withdrawal even if results of liver function tests improve. Histopathologic examination of a liver biopsy specimen is of value for diagnosis and prognosis. The liver biopsy findings, clinical course, and liver function test results are discussed, and the English-language literature on amiodarone cholestatic hepatotoxicity is reviewed.

Coincidence of Congenital Toxoplasmosis and Biliary Atresia in an Infant

Summary: A 4‐week‐old infant presenting with neonatal cholestasis was found to have congenital toxoplasmosis and biliary atresia. This is the first patient in which their coincidence is reported. Because biliary atresia can coexist with either congenital infection or inborn errors of metabolism, evaluation for an obstructive etiology of jaundice in infants with a recognized cause of intrahepatic cholestasis is necessary.

Coincidence of Congenital Toxoplasmosis and Biliary Atresia in an Infant

A 4-week-old infant presenting with neonatal cholestasis was found to have congenital toxoplasmosis and biliary atresia. This is the first patient in which their coincidence is reported. Because biliary atresia can coexist with either congenital infection or inborn errors of metabolism, evaluation for an obstructive etiology of jaundice in infants with a recognized cause of intrahepatic cholestasis is necessary.

Alcoholic Liver Disease: Pathologic, Pathogenetic and Clinical Aspects

Alcoholic liver disease includes steatosis, alcoholic hepatitis and cirrhosis. Other liver diseases of genetic origin, but with a curious association with alcohol intake, are hemochromatosis and porphyria cutanea tarda. The attribution of chronic hepatitis to alcohol intake remains speculative, and the association may reflect hepatitis C infection. Hepatic injury attributed to alcohol includes the changes reported in the fetal alcohol syndrome. Steatosis, the characteristic consequence of excess alcohol intake, is usually macrovesicular and rarely microvesicular. Acute intrahepatic cholestasis, which in rare instances accompanies steatosis, must be distinguished from other causes of intrahepatic cholestasis (e.g., drug-induced) and from mechanical obstruction of the intrahepatic bile ducts (e.g., pancreatitis, choledocholithiasis) before being accepted. Alcoholic hepatitis (steatonecrosis) is characterized by a constellation of lesions: steatosis, Mallory bodies (with or without a neutrophilic inflammatory response), megamitochondria, occlusive lesions of terminal hepatic venules, and a lattice-like pattern of pericellular fibrosis. All these lesions mainly affect zone 3 of the hepatic acinus. Other changes, observed at the ultrastructural level, are of importance in progression of the disease. They include widespread cytoplasmic shedding, and capillarization and defenestration of sinusoids. Progressive fibrosis complicating alcoholic hepatitis eventually leads to cirrhosis that is typically micronodular but can evolve to a mixed or macronodular pattern. Hepatocellular carcinoma occurs in 5 to 15% of patients with alcoholic liver disease. The clinical syndrome of alcoholic liver disease is the result of three factors--parenchymal insufficiency, portal hypertension and the clinical consequences of extrahepatic damage produced by alcohol. At the several phases of the life history of alcoholic liver disease, the individual factors play a different role. The clinical manifestations of alcoholic steatosis are mainly extrahepatic in origin. Those of alcoholic hepatitis reflect mainly parenchymal insufficiency and those of cirrhosis are mainly those of portal hypertension. Alcoholic liver injury appears to be generated by the effects of ethanol metabolism and the toxic effects of acetaldehyde, perhaps the immune responses to alcohol- or acetaldehyde-altered proteins, and questionably enhanced by viral hepatitis. Alcoholic hepatitis may be mimicked histologically, and to a varying degree clinically, by a number of conditions (obesity, diabetes, several drug-induced injuries, jejunoileal bypass, and related "shortcircuiting" of the bowel). Perhaps the most important facet of the hepatotoxicity of alcohol is its enhancement of the effects of a number of other hepatotoxic agents, among which acetaminophen is the prime example.

Neonatal Jaundice: Clinical and Ultrasonographic Findings

We reviewed the laboratory parameters, clinical information including presence or absence of stool pigmentation, and ultrasonographic findings in 67 patients with neonatal conjugated hyperbilirubinemia and liver biopsies. Hepatobiliary nuclear scintigraphy was done in 14 of the patients. Final diagnoses included extrahepatic biliary atresia, neonatal hepatitis, cystic fibrosis, metabolic liver disease, alpha 1-antitrypsin deficiency, bile duct stenosis, Alagille syndrome (arteriohepatic dysplasia), choledochal cyst, panhypopituitarism, and miscellaneous causes of intrahepatic cholestasis. A single diagnostic criterion is insufficient to distinguish the various causes of neonatal jaundice. Clinical laboratory values varied widely among patients with medical and surgical causes of jaundice. Absence of stool pigmentation was not specific for biliary atresia and was found in patients with medical causes of jaundice. Conversely, two patients with biliary atresia had pigmented stools at presentation. Ultrasonography was diagnostic only for choledochal cyst and bile duct stenosis. Nonvisualization of the gallbladder by either ultrasonography or nuclear hepatobiliary scintigraphy was nonspecific in the discrimination of medical from surgical causes of jaundice. A multidisciplinary approach to the evaluation of neonatal jaundice is necessary, since no single test or imaging modality can reliably define the cause in all cases.

A Case of Cholestasis: Benign and Recurrent and Not due to Measles

To the Editor.— In 1983 we reported in JAMA the case of a 19-year-old man who had a well-documented measles infection and cholestasis. 1 Jaundice appeared a few days after clinical symptoms of rubella. His total bilirubin level increased to 740 μmol/L, while his serum γ-glutamyltransferase level was normal. Endoscopic retrograde cholangiography showed normal biliary ducts. The usual causes of intrahepatic cholestasis were excluded. Histological study of the liver showed major centrolobular cholestasis without necrosis. Jaundice continued for 4 months, but 5 months after the onset results of liver function tests were normal. Rubella seemed to have been the most likely explanation for the cholestasis. This case had a few points in common with that reported by McLellan and Gleiner. 2 Our patient remained in good condition until September 3, 1988, when he developed a pharyngitis. He received 1500 mg/d of troleandomycin. Two days later, troleandomycin therapy was discontinued because

Causes of cholestasis in Thailand: A study of 276 consecutive patients

The causes of cholestasis in 276 patients with a total of 296 lesions were studied. Extrahepatic cholestasis was found in 58.4 percent of the patients, and 41.6 percent had intrahepatic cholestasis. Malignant disease was found in 34.8 percent of the patients (extrahepatic cholestasis in 20 and intrahepatic cholestasis in 70). Cholangiocarcinoma, especially the hilar intrahepatic type, seems to be the most prevalent in the medical literature. It is possible that the combination of opisthorchiasis and carcinogenic agents, such as nitrosamines, induce a precancerous stage at the hilar area. Some unknown factors, may be the immune system in immune surveillance that act as a catalyst leading to malignant transformation. Acute calculous cholecystitis, choledocholithiasis, and intrahepatic stones are more common in Thailand than in the western countries, and their causes have been discussed herein. The composition of stones is also different; pigment stones are found more often in Thailand. These differences between the western and oriental types of biliary calculi are significant in regard to diagnostic approach and management, and morbidity and mortality. In Thailand, Opisthorchiasis viverrini has significant influence in the development of several cholestatic diseases, such as hilar intrahepatic cholangiocarcinoma, biliary calculi, opisthorchiatic intrahepatic cysts, and aggregated dead opisthorchiatic worms blocking the biliary system. In tropical countries, infectious diseases such as virus B hepatitis; severe systemic infectious diseases such as salmonellosis; and amebiasis and tuberculosis were also important causes of intrahepatic cholestasis. In the category of congenital anomalies, the prevalence of choledochal cysts was higher than in the United States. The prevalence of other forms of congenital anomalies of the biliary system is unknown, but may be similar to the prevalence of choledochal cysts.

Microfilament Dysfunction as a Possible Cause of Intrahepatic Cholestasis

The effects of cytochalasin B on bile canalicular structure and function were examined. Three experimental models were used, cultured hepatocytes, isolated perfused liver, and in vivo infused liver. The techniques used were light and electron microscopy and, in selected instances, scanning electron microscopy, electron "stains" for microfilaments, and measurements of bile flow. Microfilament disruption and dilation of bile canaliculi were consistently found and closely paralleled a reduction in bile flow in both in vitro and in vivo infused animals. It is proposed that under normal circumstances, the microfilaments maintain the canaliculi in a contracted or partly contracted state. Hence, the microfilamentous network would provide tone to the canalicular system which would tend to reduce stagnation and facilitate the flow of bile. Removal of normal microfilament contractile function would be expected to produce canalicular ectasia and reduction of bile flow, as was observed. Microfilament dysfunction may therefore be a possible cause of intrahepatic cholestasis. Crucial to this hypothesis are the presence of actin-containing microfilaments in the pericanalicular web, and an action of cytochalasin B on their contractility. Evidence pertaining to these requirements is presented and discused.