Cholestasis is defined as stagnation, or at least a marked reduction, in bile secretion and flow. Cholestasis can be due to a functional impairment of the hepatocytes in the secretion of bile and/or due to an obstruction at any level of the excretory pathway of bile, from the level of the hepatic parenchymal cells at the basolateral (sinusoidal) membrane of the hepatocyte to the ampulla of Vater in the duodenum. Cholestatic jaundice can thus be classified into intrahepatic or extrahepatic cholestasis, depending upon the level of obstruction to bile flow. Intrahepatic cholestasis or functional cholestasis can be due to a disease involving the liver parenchymal cells and/or the intrahepatic bile ducts. Intrahepatic cholestasis can be further subclassified as intralobular (disease of liver parenchymal cells and transporter molecules) and extralobular (disease involving intrahepatic bile ducts) cholestasis. Extrahepatic cholestasis or obstructive cholestasis is due to excretory block outside of the liver, along with the extrahepatic bile ducts.
Clinically, cholestasis leads to retention of the constituents of bile in blood. The 2 major constituents of bile are bilirubin and bile acids. Thus biochemically, cholestasis is marked by the elevation of predominantly serum alkaline phosphatase. Histologically, the retention of bilirubin in the hepatocytes, bile canaliculi, or bile ducts causes bilirubinostasis and is clinically manifested as jaundice. The stagnation of bile acids, on the other hand, causes typical changes in the periportal region of the liver which is termed as cholate stasis and presents clinically as pruritus. As the excretion of bilirubin follows hepatocellular pathways different from those of bile acids, serum bilirubin level may be normal in certain cases of severe cholestasis (anicteric cholestasis), and the patient may present with only pruritus but no jaundice. Prominent features of cholestasis are pruritus and malabsorption of fat and fat-soluble vitamins.
Canalicular Membrane Changes
Genetic Defects in Bile Transporters
Canalicular/Ductular Luminal Obstruction
Cholestasis is observed across all age groups. However, in the pediatric and adolescent age group is more susceptible to cholestasis owing to immaturity of the liver. Also, there is no apparent difference in the prevalence of cholestatic jaundice between male and female. Females are at slightly higher risk of biliary atresia, drug-induced cholestasis, and intrahepatic cholestasis of pregnancy.
Cholestasis can occur either in a hepatocellular pattern where there is an impairment in bile synthesis. Bile is a highly complex, water-soluble medium. Bile formation included multiple different mechanisms of conjugation with multilevel regulation. The content of bile is transported in canaliculus via transported protein which creates a chemical and osmotic gradient through which water enters the canaliculi. Identification of abnormalities within some of these transporter proteins has led to an understanding mechanism of certain diseases better such as benign recurrent intrahepatic cholestasis (F1C1 locus gene) and progressive familial intrahepatic cholestasis (F1C2 locus gene). Failure to transport this bile salts lead to its accumulation within the liver. The strong detergent-like effect of the bile salts causes membrane injury and impairment of membrane function. Another mechanism of cholestasis is the physical obstruction to bile flow at the level of extrahepatic biliary ducts. Retained bile similarly causes hepatotoxicity.
The histologic findings are disease specific. However, in general, in hepatocellular causes of cholestasis, histology shows the presence of bile within hepatocytes and canaliculi spaces along with diffuse cholestatic injury pattern. While in the obstructive cholestatic pattern, histology shows bile plugging of interlobular bile ducts, portal expansion, and bile duct proliferation with mainly a centrilobular pattern of cholestatic injury. Retention of bilirubin (bilirubinostasis) can lead to stagnation of bile and bilirubin along cytoplasmic, canalicular, ductular or ductal regions, depending on the severity and duration of biliary obstruction. Cholate stasis corresponds to the peculiar changes in the periportal hepatocytes due to stagnation of bile acids and their detergent effects. There is hydropic swelling of hepatocytes with a clearing of their cytoplasm, and the concentration of the remaining cytoplasm in the perinuclear region with the formation of Mallory bodies and accumulation of copper-binding proteins (stained by orcein) in autophagic vacuoles. Acute complete obstruction of the extrahepatic bile ducts is manifested as portal edema and centrilobular bilirubinostasis in the early stage, followed by cholangiolitis (neutrophilic inflammation around the periportal ductules) and parenchymal bilirubinostasis which extends into the periportal areas. Chronic complete obstruction reveals all of the classic features of cholestasis, which eventually leads to secondary biliary cirrhosis. Chronic incomplete cholestasis, on the other hand, reveals the periportal and parenchymal features of cholestasis, depending on the duration of obstruction. Bilirubinostasis, however, may remain absent for long periods in chronic incomplete obstruction.
The onset is critical. Acute, sudden, and rapid onset is suggestive of acute pathology as opposed to chronic, insidious onset, which might be concerning for malignancy or other chronic etiology. While a good history is vital in a patient with new onset of jaundice, following are some of the features in history that can point toward a specific etiology.
Other clinical features observed in patients with chronic cholestasis:
The extent of jaundice can assess the degree of hyperbilirubinemia. Examination of icterus should be done in the conjunctiva, oral mucosa, as well as skin throughout the body.
Cachexia or wasting indicate either cancer or cirrhosis. Findings of diffuse lymphadenopathy especially Virchow’s nodes can be suggestive of underlying malignancy.
In chronic cholestasis scratch marks due to pruritus, melanin pigmentation, as well as xanthomas over eyelids, extensor surfaces, and palmar creases can be found. Findings of chronic liver disease, for example, spider angiomas might suggest cirrhosis. Findings of needle track markers might suggest intravenous (IV) drug use.
Large, nodular liver suggests possible hepatic metastasis. Tender hepatomegaly can be seen in viral hepatitis, congestive heart failure, and alcoholic hepatitis. In choledocholithiasis and cholecystitis, right upper quadrant (RUQ) tenderness is appreciated. Palpable, enlarged, painless gallbladder can suggest pancreatic cancer. Splenomegaly can be seen due to massive hemolysis or portal HTN. Ascites can be observed in cirrhosis due to portal HTN.
Liver Chemistry Panel
Management of cholestatic jaundice widely depends upon underlying etiology and type of cholestasis. Usually, the mainstay of obstructive cholestasis is biliary decompression. Management of hepatocellular cholestasis includes symptomatic treatment of associated symptoms while specific treatment for underlying disease process is attempted.
In cases of obstructive physiology, pruritus is relieved within 24 to 48 hours of biliary decompression. For other cases. The following medications can be attempted for symptomatic control.
Cholestyramine: Should be taken with breakfast. Pruritus is the least in the morning as pruritus factor is stored in gallbladder overnight during the morning. The dose can be repeated after breakfast depending upon response. Required dose can vary from 4 gm daily to 12 gm maximum dose daily. Patients should be kept on the minimal required dose to avoid side effects such as nausea and oily stool. Fat-soluble vitamins should be supplemented.
Ursodeoxycholic acid can be used in doses of 13 to 15 mg/kg per day to reduce itching in patients with cholestasis due to PBC and possibly in drug-associated cholestasis. Use is not studied in other causes of cholestasis.
Antihistamine medications can be used especially at night mostly for sedative effect.
Phenobarbitone can be used to relieve itching resistant to other modes of therapy.
Naloxone is an opioid antagonist is currently experimental has shown to relieve itching due to cholestasis in a randomized control trial.
Non-pharmacological treatment options include bright light therapy (based on the circadian pattern of pruritus associated with cholestasis) and plasmapheresis.
Surgical resection of greater than 15% of terminal ileum to prevent enterohepatic circulation (bile salt reabsorption) can be effective in intractable pruritus.
Finally, in cases of PBC/PSC and other causes leading to end-stage liver disease, liver transplantation can cure intractable pruritus.