Refers to a group of acquired disorders associated with progressive destruction and disappearance of the intrahepatic bile ducts and, ultimately, cholestasis.
Most adult patients who have chronic cholestasis have either primary biliary cirrhosis or primary sclerosing cholangitis.
A rare complication of drug induced liver injury marked clinically by chronic cholestasis and histologically by loss of intrahepatic bile ducts.
Usually occurs after a bout of severe cholestatic hepatitis, often with immunoallergic features.
Manifests 1 to 6 months after the onset of injury.
Typical symptoms are persistent pruritus, fatigue, jaundice, sometimes with severe dyslipidemia, hypercholesterolemia and skin xanthomata.
Arises in the setting of severe acute cholestatic hepatitis with persistent elevations in serum alkaline phosphatase and bilirubin.
Serum cholesterol levels are also raised as are serum bile acid levels.
Drugs implicated in causing VBDS include: amoxicillin/clavulanate, other penicillins, fluoroquinolones, sulfonamides, anticonvulsants, antifungal agents, nonsteroidal antiinflammatory agents, phenothiazines, and tricyclic antidepressants.
Any cause of severe acute cholestatic or mixed hepatitis may lead to the syndrome.
Often associated with immunologic and allergic features such as rash, fever, facial edema, lymphadenopathy and eosinophilia, and rarely Stevens Johnson syndrome or toxic epidermal necrolysis.
Can be progressive with almost complete loss of bile ducts with severe cholestasis and hepatic failure leading to death.
Liver transplantation may be required within 1 to 3 years of onset in severe cases.
The process may be associated with partial and reversible bile duct loss.
With clinical recovery residual chronic liver injury occurs, with pruritus and abnormal LFTs and liver biopsy shows hepatic fibrosis and a relative decrease in hepatic ducts.
Patients with mild illness may have clinical recovery without symptoms or jaundice, but may have persistent elevations of serum alkaline phosphatase and GTT and on biopsy have a relative deficiency of bile ducts.
The diagnosis of VBDS requires a liver biopsy with a sufficient number of portal areas to allow assessessment of bile duct loss.
The diagnostic criteria requires persistent elevations in serum alkaline phosphatase and bilirubin for more than 6 months after onset of drug induced liver disease, exclusion of clinical or serologic evidence of primary biliary cirrhosis, sclerosing cholangitis or graft-vs-host disease, and a liver biopsy findings of paucity of intralobular bile ducts with less than 50% of portal areas with bile duct in a biopsy with at least 10 portal areas, in a sample taken at least 3 months after onset of injury.
If there are persistent elevations in serum alkaline phosphatase and/or GGT for more than 12 months after onset of drug induced liver injury, and a liver biopsy demonstrates decreased intralobular bile ducts with <70% of portal areas with an intralobular bile duct on biopsy with at least 10 portal areas, the diagnosis is a consideration.
Symptoms include: pruritus, fatigue and hypercholesterolemia with xanthomata.
Management of itching includes use of antihistamines such as diphenhydramine and hydroxyzine, and the use of bile acid resins such as cholestyramine and colistipol to bind bile acids in the intestine.
Other less treatments for pruritus include rifampin and naltrexone which have been reported to be beneficial.
Severe hyperlipidemia with painful xanthomata may require plasma exchange for management.
Intractable pruritus can be an indication for liver transplantation.
No evidence corticosteroids are beneficial and may worsen the metabolic effects of end stage liver disease and cholestasis.
Ursodiol is almost always used and there is anecdotal reports of benefit.
The process can slowly resolve and a major focus of management should be avoidance of further injury.
There should be attention to nutrition and vitamin and mineral replacement.
A number of patients with VBDS due to medications eventually develop cirrhosis, end stage liver disease and will require liver transplantation.
Vanishing Bile Duct Syndrome
VBDS is a rare but serious outcome and complication of drug induced liver injury marked clinically by chronic cholestasis and histologically by loss of intrahepatic bile ducts.
Typically occurs after a bout of severe cholestatic hepatitis, often with immunoallergic features.
A complication of acute drug induced liver injury, generally becoming manifest 1 to 6 months after the onset of injury.
Typical symptoms are persistent pruritus, fatigue and jaundice, sometimes associated with severe dyslipidemia, hypercholesterolemia and skin xanthomata.
Skin xanthomata can be painful, particularly when present on palms and soles.
Typically arises in the setting of severe acute cholestatic hepatitis in which there is an inadequate recovery as shown by persistent elevations in alkaline phosphatase levels and bilirubin.
Often occurs despite a decrease in serum aminotransferase levels into the normal or near-normal range.
Serum cholesterol levels are also raised as are serum bile acid levels.
Drugs that have been implicated in causing VBDS include amoxicillin/clavulanate, other penicillins, fluoroquinolones, sulfonamides, antifungal agents, nonsteroidal antiinflammatory agents, phenothiazines, tricyclic antidepressants and aromatic anticonvulsants.
Any cause of severe acute cholestatic or mixed hepatitis may lead to VBDS.
Other conditions that can mimic or cause vanishing bile duct syndrome include graft-vs-host disease, Hodgkin’s disease, sclerosing cholangitis and primary biliary cirrhosis.
A pathological diagnosis although can be diagnosed clinically without liver histology.
Furthermore, there are great variations in severity and outcome of VBDS.
Most cases arise within a few months of onset of severe cholestatic hepatitis.
Process often associated with immunoallergic features such as rash, fever, facial edema, lymphadenopathy and eosinophilia.
May be associated with Stevens Johnson syndrome or toxic epidermal necrolysis.
Can be progressive, with almost complete loss of bile ducts accompanied by severe cholestasis and hepatic failure leading to death or need for liver transplantation within 1 to 3 years of onset.
In other situations, the bile duct loss is only partial and not progressive and ultimately reverses, at least partially.
In many instances, clinical recovery occurs but there is evidence of residual chronic liver injury, with mild pruritus and abnormal serum enzymes and liver biopsy showing hepatic fibrosis and a relative decrease in hepatic ducts.
In the mildest types, patients may recover clinically and no longer have symptoms or jaundice, but exhibit persistent alkaline phosphatase and GGT elevations and have a relative paucity of bile ducts if a liver biopsy is performed.
Diagnosis in its milder forms, requires expertise in hepatic pathology and a liver biopsy with adequate numbers of portal areas to fully assess bile duct loss.
Aspects for diagnosis include:
Persistent elevations in serum alkaline phosphatase and bilirubin for more than 6 months after onset of drug induced liver disease.
Absence of clinical or serologic evidence of primary biliary cirrhosis, sclerosing cholangitis and graft-vs-host disease.
Liver biopsy findings of paucity of intralobular bile ducts with <50% of portal areas with bile duct in a biopsy with at least 10 portal areas.
Mild, or partial or syndrome may be accompanied by lesser decrease in bilec ducts, with 50-75% of portal areas having an identifiable intralobular bile duct.
Syndrome may be associated with pruritus, fatigue and hypercholesterolemia with xanthomata.
Pruritus can be managed with antihistamines, and bile acid resins that can bind and trap pruritogenics in the intestine.
Other less well established treatments for pruritus include rifampin and naltrexone.
Hyperlipidemia may require therapy as well, but it responds minimally statins, which are best avoided.
Severe hyperlipidemia with painful xanthomata may require plasma exchange for management.
The presence of severe intractable pruritus can be an indication for liver transplantation.
Corticosteroids are often used in treatment of VBDS, but there is no evidence that they are beneficial.
Ursodiol is almost universally used in the treatment of VBDS, but only anecdotal reports have suggested that they are beneficial.
VBDS can slowly resolve on its own.
The major focus of management is avoidance of further injury, attention to nutrition and vitamin and mineral replacement
A number of patients with VBDS due to medications eventually develop cirrhosis and end stage liver disease requiring liver transplantation.
Drugs associated with VBDS Syndrome include:
Antibiotics:
Penicillins Amoxicillin, Amoxicillin/Clavulanic Acid, Flucloxacillin
Cephalosporins:
Cefdinir, Cefazolin, Cephalexin
Fluoroquinolones:
Ciprofloxacin, Levofloxacin, Moxifloxacin
Sulfonamides:
Trimethoprim-Sulfamethoxazole
Macrolides Azithromycin, Erythromycin
Lincomycins Clindamycin
Tetracyclines
Carbapenems Meropenem
Antiviral Agents Nevirapine
Antifungal Agents Itraconazole, Terbinafine
Antihelmitic agents Thiabendazole
Anticonvulsants Carbamazepine, Oxycarbazine, Phenytoin, Valproate, Phenobarbital, Lamotrigine, Zonisamide
Antidepressants Amitriptyline, Imipramine, Sertraline
Antipsychotic agents Olanzapine, Haloperidol, Phenothiazines
Lipid lowering agents, Atorvastatin, Fenofibrate
Rheumatologic agents Allopurinol, Azathioprine, Infliximab, Gold
Antineoplastic agents Temozolomide, Thalidomide, Lenalidomide
Hormones Anabolic Steroids, Estrogens
NSAIDs-Ibuprofen, Acetaminophen, Phenylbutazone
Anti-diabetic agent Tolbutamide
Gastrointestinal agents Cimetidine, Metoclopramide, Lansoprazole, Omeprazole
Respiratory agents Cromolyn, Montelukast
Cardiovascular agents Hydrochlorothiazide, Enalapril