Drug-Induced Vanishing Bile Duct Syndromes
Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso in The Pathophysiology of Biliary Epithelia, 2020
Drug-induced vanishing bile duct syndromes are part of the spectrum of drug-induced cholestatic diseases. The term cholestasis refers to a reduction or an arrest in bile secretion and/or bile flow. Cholestasis may be due to three different mechanisms: alteration of bile secretion by the hepatocyte (hepatocellular cholestasis). Hepatocellular cholestasis may be ‘pure’, i.e., without hepatocellular damage (as is the case in estrogen-induced cholestasis), or associated with some degree of hepatocellular damage, i.e., hepatitis. Hepatitis is described as cholestatic when cholestasis dominates the picture. This is frequent in drug-induced cholestasis.obstruction of intrahepatic bile ducts. In drug-induced cholestasis, the site of injury is usually the bile ductules (cholangiolitis) or the interlobular, portal bile ducts (cholangitis). Bile ductules are the finest, most peripheral branches of the biliary tree, connecting the canaliculi with the interlobular bile ducts.obstruction of extrahepatic bile ducts.
Erythromycin
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Hepatotoxicity is a rare but serious adverse effect of erythromycin. Initially, this was thought to occur after administration of erythromycin estolate, but not after administration of other erythromycin preparations (Masel, 1962; Sherlock, 1968). It was postulated that the propionyl ester linkage at the 2′ position conferred this property on the estolate and that there was no cross-sensitivity with other erythromycin preparations (Tolman et al., 1974). Jaundice usually occurs about 10–12 days after starting treatment, but it may occur within 1 or 2 days in patients who had previously experienced the drug (Robinson, 1961; Gilbert, 1962). Some patients may experience severe abdominal pain, which may lead to an erroneous diagnosis of cholelithiasis (Oliver et al., 1973). Nausea and abdominal pain are initial symptoms, followed by fever (50%). Approximately 75% of patients develop eosinophilia (> 500 cells/mm3) and uniformly elevated transaminase levels. Liver function tests revert to normal within days after discontinuation of the drug but may recur after rechallenge (Eichenwald, 1986). Occasionally, pruritus and a rash may recur. Jaundice may be clinical or subclinical, and hepatic enlargement is usually present. Liver function tests usually indicate cholestasis, and the mechanism of this toxicity may represent either a hypersensitivity or toxic reaction resulting from the formation of nitrosoalkanes (Pessayre et al., 1985). Liver histology usually reveals a picture of intrahepatic cholestasis.
Mechanisms of Fibril Formation and Cellular Response
Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin in XIth International Symposium on Amyloidosis, 2007
The expression of this condition appears to be highly conserved among the several families analyzed. Isolated cholestasis is the most common sign of the disease and may be a hint to early diagnosis. Liver involvement is almost invariably asymptomatic over time and hepatomegaly develops only in a minority of patients. In seven patients there was evidence of progressive portal hypertension and four ultimately died of liver failure. Renal involvement invariably manifests as a tubulointerstitial disorder, characterized by a defective urine-concentrating ability and moderate poliuria. Glomerular proteinuria is absent in most patients, although it may develop over time and appears to parallel the progression to end-stage renal failure, which was observed in 9 patients (13%). Moderate to severe hypertension is almost invariably present. Heart involvement is rarely observed, although a mild hypertrophy is observed, that can be attributed to the long-lasting hypertension.
Kuhuang injection exerts a protective effect by activating PPAR-γ in an in vitro model of chlorpromazine-induced cholestatic liver injury constructed by tissue engineering
Published in Pharmaceutical Biology, 2022
Qiao Wu, Zhongping Duan, Long Huang, Zhijie Li
Drug-induced liver injury (DILI) is a common clinical adverse drug reaction and an important factor in drug development failure and withdrawal (Kullak-Ublick et al. 2017). Cholestatic injury and mixed hepatocytic/cholestatic injury constitute the two main subtypes of DILI and may account for 50% of all DILI cases (Shen et al. 2019). Drug-induced cholestasis (DRIC) may manifest clinically as pruritus, malaise, darkened urine, and jaundice and is often asymptomatic in the early stages, eventually manifesting as elevated serum alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (GGT) levels and possibly progressing to hyperbilirubinemia, which can lead to liver failure or even death in severe cases (Padda et al. 2011). At present, effective drugs for the clinical treatment of cholestasis are lacking. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the clinically approved drugs for cholestasis and are recognized to have certain curative effects, but their therapeutic effect is limited, as there are large individual differences in their effects (Santiago et al. 2018). Thus, the treatment strategies for DRIC are not ideal. Therefore, it is necessary to develop new drugs for the treatment of cholestatic liver injury. Furthermore, traditional Chinese medicine has received increasing attention in the treatment of DRIC (Li et al. 2019; Wang et al. 2020; Hua et al. 2021).
Intrahepatic cholestasis of pregnancy: from an obstetrician point of view
Published in Journal of Obstetrics and Gynaecology, 2022
Mohsen M. A. Abdelhafez, Karim A. M. Ahmed, Win Win Than, Dg Marshitah Pg Baharuddin, Fairrul Kadir, Saffree Jeffree, Mohammad Firdaus Hayati, Mohd Nazri Bin Mohd Daud, Aya M. Eldiastey, Kai Xin Tay
Physical examination will show lack of any primary skin lesions, which questioned including ICP among pregnancy dermatoses, only excoriation marks due to severe scratching, are detected. The mechanism behind the pruritus-induced cholestasis is not clearly understood, it was hypothesised to be due to direct pruritogenic effects of bile acids on the skin, others attribute it to an unknown substance released from damaged liver cells by the effect of accumulated bile into general circulation (Ghent et al. 1977). Other ICP symptoms may include nausea, anorexia and right hypochondrial pain. A tinge of jaundice will be observed in 10–15% of patients, usually following pruritus by 4weeks (Kondrackiene and Kupcinskas 2008), steatorrhoea, usually mild, can occur secondary to malabsorption of fat, very seldom for steatorrhoea to be that severe, to result in vitamin K deficiency. Some women may present with systemic manifestations of cholestasis as pale stool and dark urine in addition to becoming jaundiced (Williamson and Geenes 2014b).
Personalizing liver targeted treatments and transplantation for patients with alpha-1 antitrypsin deficiency
Published in Expert Review of Precision Medicine and Drug Development, 2021
Anita Pye, Sheeba Khan, Tony Whitehouse, Alice M Turner
Four genetic cholestatic liver diseases, including AATD, are currently being investigated in an ongoing 20-year observational prospective study (LOGIC) to provide a better understanding of their causes and effects (NCT00571272). The study enrolls participants from infancy through to adults of up to 25 years of age who have, or are suspected of having, genetic cholestatic liver disease. Preliminary results from 269 subjects enrolled between 2008 and 2012 have shown that many patients with AATD presenting with elevated liver tests and jaundice improve spontaneously [32] and therefore may not need any therapeutic intervention. Four rare genetic liver disorders, Alagille Syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), bile acid synthesis and metabolism defects and AATD account for approximately 20% to 30% of all infant cases of cholestasis [33]. Cholestasis involves a reduction or obstruction of bile flow from the liver to the small intestine and can cause significant growth problems during childhood. If left untreated it can cause serious liver problems, the need for liver transplantation, and potentially death.
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