Cholestatic disorders

Cholestasis refers to the impairment in bile formation or flow which can manifest clinically with fatigue, pruritus, and jaundice.


The differential diagnosis of cholestatic liver diseases is broad.


Cholestasis etiologies  vary by the anatomical location of the defect and its acuity of presentation. 


Causes of Acute and Chronic Cholestasis:

Biliary obstruction- cholelithiasis 

Primary sclerosing cholangitis


Secondary sclerosing cholangitis

Drug-induced liver injury

Primary biliary cholangitis


Drug-induced liver injury

TPN-associated cholestasis TPN-associated cholestasis

Intrahepatic cholestasis of pregnancy

Congestive hepatopathy

Alcoholic hepatitis

Biliary atresia


Infiltrative disorders

• Sarcoidosis

• Mastocytosis

• Lymphoma

• Fungal infections

• Tuberculosis

Genetic disorders

• Progressive familial intrahepatic cholestasis

• Benign recurrent intrahepatic cholestasis

• Alagille syndrome

• Cystic fibrosis

TPN = total parenteral nutrition.

Bbiochemical evidence of cholestasis includes increases in serum alkaline phosphatase (ALP) and gamma-glutamyltranspeptidase (GGT), followed by onset of conjugated hyperbilirubinemia. 


If cholestasis persists for longer than 3 to 6 months it is considered to be chronic.


Notably, some causes of acute cholestasis, such as:

Total parenteral nutrition (TPN)-associated cholestasis or drug-induced liver injury (DILI), have the potential for the development of chronic cholestasis.


Cholestatic disorders are defined as intra- or extrahepatic. 


Intrahepatic cholestasis is caused by defects in bile canaliculi, hepatocellular function, or intrahepatic bile ducts.


Extrahepatic cholestasis affect the extrahepatic ducts, common hepatic duct, or common bile duct.


Primary sclerosing cholangitis, can affect both the intrahepatic and extrahepatic bile ducts. 


Patients with cholestasis may develop jaundice, acholic or clay-colored stools, darkening of the urine, and pruritus. 


Patients with extrahepatic cholestasis may have symptoms of biliary colic or have a palpable gall bladder.


Jaundice accompanied by fever and abdominal pain is characteristic of cholangitis. 


Chronic cholestasis increases risk for several complications:  impairs the absorption of fat-soluble vitamins and therefore predisposes to metabolic bone disease; Primary biliary cholangitis is associated with hyperlipidemia and cutaneous lipid deposits, which manifest as xanthomas and xanthelasmas; progression to cirrhosis with portal hypertension, ascites, spider angiomata, and gynecomastia.


Choledocholithiasis, the presence of gallstones within the common bile duct 

is  among the most common causes of acute cholestasis. 


Most cases of choledocholithiasis occur secondary to migration of gallstones from the gallbladder into the CBD and are composed largely of cholesterol stones.


Primary common bile duct stones are less common.


Primary common bile duct stones

are usually brown-pigmented stones composed of calcium bilirubinate. 


Risk factors for primary choledocholithiasis are bile stasis, papillary stenosis, dilation of the CBD, periampullary diverticulum, and recurrent or persistent infection of the biliary system.


Choledocholithiasis may be asymptomatic, but most present with right upper-quadrant or epigastric pain, jaundice, fever, nausea, or vomiting.


Importantly, early biochemical features of biliary obstruction are not cholestatic.


Drug-Induced Liver Injury (DILI) accounts for approximately 52% of cases of fulminant hepatic failure in the United States.


Drug-Induced Liver Injury can be categorized into hepatocellular, cholestatic, or mixed cholestatic and hepatocellular injury. 


The category of DILI is defined according to the R ratio.


(ALT)/upper limit of normal for ALT; patient’s ALP/upper limit of normal for ALP. 


An R ratio of greater than 5 defines hepatocellular DILI, whereas cholestatic DILI is characterized by an R ratio of less than 2. 


DILI is characterized as mixed if the R ratio is between 2 and 5.


Cholestatic injury accounts for approximately 30% of cases of DILI.


Antimicrobial agents followed by 

supplements are the most common causes of nonacetaminophen-induced DILI.


Herbal products are most often responsible for DILI  in Asian countries.


Medications associated with cholestatic DILI include,  antibiotics (amoxicillin-clavulanate, macrolides, trimethoprim/sulfamethoxazole), antifungals, anabolic steroids, antineoplastic agents, oral contraceptives, and psychotropic drugs such as chlorpromazine.


Management of DILI relies on discontinuation of the offending medication. 


The majority of patients with DILI will experience complete recovery.


Jaundice may take months to resolve after cholestatic DILI. 


In acute liver failure due to nonacetaminophen drug-induced liver injury, N-acetylcysteine administration may improve transplant-free survival.


Cholestatic injury has a better prognosis than hepatocellular DILI, but it is more likely to persist and lead to chronic injury (31% vs 13%).


Cholestasis is a common with sepsis and may occur in up to 40% of critically ill patients.


Jaundice with critical illness is often multifactorial: hemolysis, disseminated intravascular coagulation, heart failure, renal insufficiency, and drug toxicity.


The degree of jaundice is correlated with increased mortality in critically ill patients.

Sepsis Induced  impaired  bile flow in the is the primary driver of cholestasis. 


Inflammatory mediators, including  lipopolysaccharide, impair the gene expression and activity of proteins.


These proteins transport bile salts into hepatocytes and subsequently excrete them into bile canaliculi.


Endotoxins impair clearance of both conjugated and unconjugated bilirubin.


Hemolysis during sepsis may propagate cholestasis by overwhelming the liver’s ability to uptake and secrete bilirubin.


Sepsis-induced cholestasis is associated with bilirubin levels typically range from 2 to 10 mg/dL. 


Serum alkaline phosphatase rarely exceeds 2 to 3 times the upper limit of normal and is accompanied by modest elevations in serum aminotransferases. 


Differential diagnosis for cholestasis secondary to sepsis includes: biliary obstruction and drug induced liver injury.


Treatment of cholestasis secondary to sepsis is appropriate antibiotic therapy.


Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus, elevated serum aminotransferase levels, and increased total serum bile acids, which presents in the late second or third trimester of pregnancy. 


Intrahepatic cholestasis of pregnancy usually resolve following delivery, but may recur with subsequent pregnancies.


Intrahepatic cholestasis of pregnancy 

incidence has significant geographic variation: from <1% in Australia, Canada, and parts of Europe, to 27.6% in parts of Chile.


Intrahepatic cholestasis of pregnancy 

likely reflects a combination of genetic, environmental, and hormonal factors. 


Women with underlying chronic liver disease, such as hepatitis C and nonalcoholic fatty liver disease, may be at increased risk for intrahepatic cholestasis.


Intrahepatic cholestasis of pregnancy 

manifests with pruritus of the palms and soles, which may progress to a generalized process.


With Intrahepatic cholestasis of pregnancy  abdominal discomfort, jaundice, and steatorrhea can occasionally develop. 


The elevation in the serum bile acids constitutes the most sensitive and specific diagnostic indicator for Intrahepatic cholestasis of pregnancy .


In Intrahepatic cholestasis of pregnancy maternal bile acids cross the placenta, and accumulate in the fetus and amniotic fluid.


The impaired normal transplacental gradient of bile acids increases risk of  preterm delivery, stillbirth, meconium staining of amniotic fluid, and neonatal respiratory distress syndrome.


Neonatal risks correlates with increasing maternal serum bile acid levels, particularly when they exceed 40 micromol/L. 


Intrahepatic cholestasis of pregnancy 

does not appear to have long-term impact on maternal morbidity and mortality.


Ursodeoxycholic acid (UDCA) 10 to 15 mg/kg per day is the primary treatment for Intrahepatic cholestasis of pregnancy .


Ursodeoxycholic acid improves pruritus and liver biochemistries, but  no improvement in perinatal outcomes.

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