Continuing Education Activity
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. Cholestatic jaundice can be classified into intrahepatic or extrahepatic cholestasis, depending upon the level of obstruction to bile flow. Clinically, cholestasis leads to retention of the constituents of bile in blood. Prominent features of cholestasis are pruritus and malabsorption of fat and fat-soluble vitamins. This activity reviews the evaluation and management of cholestatic jaundice and highlights the role of interprofessional team in the care of affected patients.
Objectives:
Review the pathophysiology of cholestatic jaundice.
Outline the differential diagnosis of cholestasis.
Describe the diagnostic approach to a patient with suspected cholestatic jaundice.
Explain a well-coordinated interprofessional team approach to provide effective care to patients affected by cholestatic jaundice.
Introduction
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 [1][2][3][4]
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.
Etiology
Extrahepatic Cholestasis
- Choledocholithiasis
- Benign bile duct strictures
- Primary or secondary sclerosing cholangitis
- Mirizzi syndrome
- Cholangiocarcinoma
- Pancreatic cancer
- Ampullary adenoma/carcinoma
Intrahepatic Cholestasis
Hepatocellular Causes
- Viral hepatitis
- Acute alcoholic hepatitis
- Parenteral nutrition
- Intrahepatic atresia (infantile cholangiopathy)
- Zellweger syndrome
Canalicular Membrane Changes
- Medication (contraceptive pills, antibiotics, antithyroid drugs, sulphonamides)
- Cholestasis in pregnancy
Genetic Defects in Bile Transporters
- Benign recurrent intrahepatic cholestasis (BRIC)
- Progressive familial intrahepatic cholestasis (PFIC)
Canalicular/Ductular Luminal Obstruction
- Cholestasis due to sickle cell disease
- Hereditary protoporphyria
- Bacterial infections, sepsis
- Cystic fibrosis
Ductopenia
- Familial, drug-induced, chronic allograft rejection, Hodgkin disease, sarcoidosis, primary sclerosing cholangitis, primary biliary cholangitis
Epidemiology
Cholestasis is observed across all age groups. However, in the pediatric and adolescent age group is more susceptible to cholestasis owing to the immaturity of the liver. Also, there is no apparent difference in the prevalence of cholestatic jaundice between male and female [4]. Females are at slightly higher risk of biliary atresia, drug-induced cholestasis, and intrahepatic cholestasis of pregnancy.
Pathophysiology
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.
Histopathology
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 [5]. Acute complete obstruction of the extrahepatic bile ducts is manifested as portal edema and centrilobular bilirubinostasis in the early stage, followed by cholangitis (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.
History and Physical
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.
- Presence of pain, specifically epigastric or right upper quadrant pain before the onset of jaundice might suggest choledocholithiasis or cholecystitis causing Mirrizi syndrome
- Presence of fever is highly suggestive of cholangitis
- The onset of jaundice after any hepatobiliary surgery might indicate, bile duct injury, bile duct leak. Jaundice is not always present in cholestasis
- Any history of critical illness or shock that can cause cholestasis of sepsis
- Any recent new medication use, especially antibiotics which can cause cholestasis
- Insidious onset of jaundice with nausea, vomiting, and prodrome phase is suggestive of viral hepatitis. History of prior travel, sexual contact, blood transfusion, and major surgery as well as the history of intravenous (IV) drug use can support this diagnosis
- Family or personal history of any autoimmune disease can point toward PSC or PBC
Other clinical features observed in patients with chronic cholestasis:
- Itching: The itching may be misdiagnosed as being due to a primary dermatological condition, particulalrly when there is no jaundice in some patients with cholestasis. Itching is typical in chronic cholestasis. Better in the morning and gets worse throughout the day after intake of food in the morning. During night time, fasting permits concentration of biliary elements decreases leading to improvement of itching in the morning.
- Fatigue: About 70% to 80% patients with chronic fatigue suffer from fatigue. Underlying abnormal serotonergic neurotransmission or neuroendocrine defects in the corticotrophin hormone axis are believed to be underlying etiology.
- Fat-soluble vitamins: Bile is necessary for absorption of ingested fat-soluble vitamins (A, D, E, and K). In chronic cholestasis, deficiency of these vitamins occurs leading to clinical features of their deficiency.
- Xanthomas: Flat or slightly raised yellow skin deposits are usually present around the eyes but can be present in palmar creases and other parts of the body.
Physical Examination
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.
General Examination
Cachexia or wasting indicate either cancer or cirrhosis. Findings of diffuse lymphadenopathy especially Virchow’s nodes can be suggestive of underlying malignancy.
Skin Examination
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.
Abdominal Examination
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.
Evaluation
Laboratory [6][7][8][9]
Liver Chemistry Panel
- Serum total and fractioned direct bilirubin should be obtained. In cholestasis, predominantly direct hyperbilirubinemia (more than 50% of total bilirubin) is observed. Serum alkaline phosphatase is also evaluated 3 times more than the upper normal limit in cholestasis, while normal or mild elevation in transaminases (ALT/AST) is a pure form of cholestatic jaundice. Serum albumin is usually normal except in cirrhosis and chronic liver disease where albumin is decreased.
Hematology
- Leukocytosis is found in cholangitis, alcoholic hepatitis, and underlying malignancy.
- Acute severe anemia can be found due to hemolysis. Evaluation of peripheral smear, reticulocyte count can help to differentiate. Chronic anemia can be seen in cirrhosis or underlying malignancy.
- Elevated prothrombin time can be seen with cholestasis which rapidly reverses with vitamin K supplementation as opposed to patients with cirrhosis.
Radiological Evaluation
- Abdominal ultrasound can help to identify if there is any biliary ductal dilation and help differentiate hepatocellular causes of cholestasis (where ducts will be normal size) versus biliary obstruction (where ducts will be dilated).
- If dilated biliary ducts are encountered on initial ultrasound, then magnetic resonance cholangiopancreatography can be used to assess bile ducts to identify stone, stricture vs. malignancy. CT scan can be helpful as well; however, MRI has better sensitivity.
Liver Biopsy
- Helpful in intrahepatic cholestasis to evaluate for various possible underlying etiologies.
Treatment / Management
Management of cholestatic jaundice widely depends upon underlying etiology and type of cholestasis. Usually, the mainstay of obstructive cholestasis is biliary decompression [10][11][12]. Management of hepatocellular cholestasis includes symptomatic treatment of associated symptoms while specific treatment for the underlying disease process is attempted.
Biliary Decompression
- In common bile duct stones, endoscopic sphincterotomy with or without stent placement can relieve the obstruction. Similarly, in benign CBD strictures, stricture dilation and stent placement can relieve the obstruction.
- In malignant obstruction, depending upon the stage of disease and the operative candidacy of the patient, surgical resection of the obstructive lesion is preferred. If complete resection is not possible, surgical hepaticojejunostomy and the Roux-en-Y bypass is an option. If a patient is not a surgical candidate, either palliative CBD stent is placed endoscopically (usually metal stent). If endoscopic stent placement is not successful, a percutaneous transhepatic cholangiography tube can be placed for biliary decompression. Antibiotics are considered in pre and post biliary decompression phase to reduce the risk of sepsis.
Medical Management
Pruritus
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.
Differential Diagnosis
Enhancing Healthcare Team Outcomes
Because there are many causes of cholestatic jaundice, most of which are serious, the disorder is best managed by an interprofessional team that includes the primary care provider, nurse practitioner, gastroenterologist, general surgeon, radiologist, and the pathologist. 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 the underlying disease process is attempted. The outcomes of patients with cholestatic jaundice depend on the cause. For those with a benign cause like a gallstone the outcomes are good but in those with malignancy, the outcomes are somewhat grave [7][13].
Cholestatic Jaundice