Cholestatic Jaundice

Etiology

Extrahepatic Cholestasis

Extrahepatic or obstructive cholestasis is due to an excretory block outside the liver and the extrahepatic bile ducts secondary to conditions including:

• Choledocholithiasis
• Benign bile duct strictures
• Primary or secondary sclerosing cholangitis
• Mirizzi syndrome
• Cholangiocarcinoma
• Pancreatic cancer
• Ampullary adenoma/carcinoma [6]

Intrahepatic Cholestasis

Intrahepatic or functional cholestasis is typically caused by conditions involving the liver parenchymal cells or the intrahepatic bile ducts, including:

• Hepatocellular causes
  • Viral hepatitis
  • Acute alcohol-related hepatitis
  • Parenteral nutrition
  • Intrahepatic atresia (infantile cholangiopathy)
  • Zellweger syndrome
• Canalicular membrane changes
  • Medication (eg, contraceptive pills, antibiotics, antithyroid drugs, sulfonamides) [7]
  • Cholestasis of pregnancy
• Genetic defects in bile transporters
  • Benign recurrent intrahepatic cholestasis
  • Progressive familial intrahepatic cholestasis
• Canalicular and 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 (PSC), primary biliary cholangitis (PBC) [6]

Epidemiology

Cholestasis can be observed in all age groups. However, due to the immaturity of the liver, the pediatric and adolescent age groups are more susceptible to cholestasis. No significant difference in the prevalence of cholestatic jaundice between males and females has been reported.[4] However, females are at a slightly higher risk of biliary atresia, drug-induced cholestasis, and intrahepatic cholestasis during pregnancy.

Pathophysiology

Cholestasis can occur in a hepatocellular pattern involving the complex bile synthesis and flow mechanism. Bile is a highly complex, water-soluble medium. Bile formation includes multiple different mechanisms of conjugation with multilevel regulation. The content of bile is transported in canaliculi via transport proteins, creating a chemical and osmotic gradient through which water enters the canaliculi. Identifying abnormalities within some of these transporter proteins has led to an improved understanding of the mechanism of certain diseases, including benign recurrent intrahepatic cholestasis (F1C1 locus gene) and progressive familial intrahepatic cholestasis (F1C2 locus gene).

Failure to transport bile salts leads 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 of cholestatic jaundice are disease-specific. In patients with cholestasis secondary to hepatocellular causes, histology shows bile within hepatocytes and canaliculi spaces along with a diffuse cholestatic injury pattern. In cases due to obstructive cholestasis, histologic characteristics of bile plugging interlobular bile ducts, portal expansion, and bile duct proliferation are typically observed, with mainly a centrilobular pattern of cholestatic injury.

Retention of bilirubin (ie, 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 changes in the periportal hepatocytes due to the stagnation of bile acids and their detergent effects. Hydropic swelling of hepatocytes with a clearing of their cytoplasm is demonstrated, and the remaining cytoplasm concentration in the perinuclear region with the formation of Mallory bodies in addition to copper-binding protein accumulation, stained by orcein, in autophagic vacuoles.[8] 

Acute complete obstruction of the extrahepatic bile ducts is manifested as portal edema and centrilobular bilirubinostasis in the early stage, followed by cholangitis (ie, neutrophilic inflammation around the periportal ductules) and parenchymal bilirubinostasis which extends into the periportal areas. Chronic complete obstruction reveals all the classic features of cholestasis, which eventually leads to secondary biliary cirrhosis. On the other hand, chronic incomplete cholestasis 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

Clinical History

Identifying additional associated acute or chronic clinical features in patients with cholestatic jaundice is essential to diagnosing the underlying etiology. A rapid onset suggests acute pathology, while a gradual and insidious onset may indicate malignancy or other chronic causes. A thorough history is crucial for a patient with a new onset of jaundice. Historical features that may indicate a specific etiology include:

• Pain, especially in the epigastrium or right upper quadrant, before the onset of jaundice might suggest choledocholithiasis or cholecystitis, which causes Mirizzi syndrome.
• Fever is highly suggestive of cholangitis.
• The onset of jaundice after any hepatobiliary surgery may indicate bile duct injury or bile duct leak; however, jaundice is not always present in cholestasis.
• Any history of critical illness or shock may result in cholestasis of sepsis.
• Any recent medication use (eg, antibiotics) can cause cholestasis.
• The insidious onset of jaundice with nausea, vomiting, and prodrome phase is suggestive of viral hepatitis. A history of prior travel, sexual contact, blood transfusion, or intravenous drug use can support this diagnosis.
• A family history or personal history of any autoimmune disease can indicate PSC or PBC.

Other clinical features observed in patients with chronic cholestasis include:

• Pruritus: Pruritus is commonly associated with chronic cholestasis, although it is often misdiagnosed as a primary dermatological condition, particularly in patients without jaundice. Patients typically report that the pruritus is better in the morning and worse at night; it may also occur intermittently throughout the disease process. This itching may be secondary to pruritogenic bile salts, which are elevated in cholestatic liver conditions that accumulate under the skin.
• Fatigue: Approximately 70% to 80% of patients with chronic cholestasis have fatigue that is thought to originate in the central nervous system and is related to underlying abnormal serotonergic neurotransmission or neuroendocrine defects in the corticotrophin hormone axis. However, the presence or severity of fatigue does not correlate to disease state or other disease-related biomarkers.
• Fat-soluble vitamin deficiency symptoms: Bile is necessary to absorb ingested fat-soluble vitamins (A, D, E, and K). In chronic cholestasis, a deficiency of these vitamins may occur, leading to clinical features of their deficiency.
• Xanthomas: Flat or slightly raised yellow skin (lipid-laden) deposits are usually present around the eyes but can be present in palmar creases and other body parts.

Physical Examination

The extent of jaundice generally reflects the degree of hyperbilirubinemia. Icterus may be seen on examination in the conjunctiva, oral mucosa, and skin throughout the body. Cachexia or wasting noted on general examination may indicate cancer or cirrhosis. Findings of diffuse lymphadenopathy, especially Virchow’s node, can suggest underlying malignancy.

Additionally, in chronic cholestasis, skin findings include excoriations due to pruritus, melanin pigmentation, xanthomas of the eyelids, extensor surfaces, and palmar creases. The presence of spider angiomas might suggest chronic liver disease or cirrhosis. Abdominal examination may demonstrate a large, nodular liver suggestive of hepatic metastasis. Tender hepatomegaly may be seen in viral hepatitis, congestive heart failure, and alcohol-related hepatitis. In choledocholithiasis and cholecystitis, tenderness in the right upper quadrant may be appreciated. Splenomegaly can be seen due to massive hemolysis or portal hypertension. Ascites can be observed in cirrhosis due to portal hypertension.

Evaluation

Diagnostic studies used to evaluate cholestatic jaundice involve a combination of clinical examination, liver function tests, imaging studies like ultrasound or magnetic resonance cholangiopancreatography (MRCP), and sometimes liver biopsy.[9][10][11][12] 

Liver Chemistry Panel

Serum total and fractioned direct bilirubin should be obtained. A predominantly direct hyperbilirubinemia (more than 50% of total bilirubin) is observed in cholestasis. Serum alkaline phosphatase is often elevated 3 times greater than the upper standard limit of normal, while the hepatic transaminases may be normal or only mildly elevated. Serum albumin is usually normal except in cirrhosis and late chronic liver disease.

Hematology

Hematologic findings can assist in identifying the etiology of cholestatic jaundice, including:

• Leukocytosis: This finding may indicate cholangitis, alcohol-related hepatitis, and underlying malignancy.
• Acute severe anemia: Severe anemia may occur due to hemolysis. Evaluation of peripheral smear and reticulocyte count can help differentiate between these 2 entities. Chronic anemia can be seen in cirrhosis or underlying malignancy.
• Elevated prothrombin time: This finding can be seen with cholestasis, which rapidly reverses with vitamin K supplementation compared to patients with cirrhosis and hepatic synthetic dysfunction.

Radiological Evaluation

Abdominal ultrasound can help identify biliary ductal dilation and differentiate between hepatocellular causes of cholestasis (where the ducts are normal) and biliary obstruction (where the ducts are dilated). If dilated biliary ducts are encountered on initial ultrasound, MRCP can be used to assess the bile ducts further and identify stones, strictures, or features of malignancy. While a computed tomography scan can be helpful, MRCP has better sensitivity.

Liver Biopsy

A liver biopsy can be helpful in cases of suspected intrahepatic cholestasis when there is diagnostic uncertainty.

Treatment / Management

The management of cholestatic jaundice depends upon the underlying etiology. The mainstay of obstructive cholestasis is biliary decompression.[13][14][15][16][17] Management of hepatocellular cholestasis includes treatment of the underlying disease and associated symptoms.(A1)

Biliary Decompression

Endoscopic sphincterotomy, with or without stent placement, can relieve obstruction due to bile duct stones. Similarly, dilation and stent placement can alleviate the obstruction in benign common bile duct strictures. Surgical resection of the obstructive lesion is preferred in the case of malignant obstruction and depends upon the disease stage and the patient's operative candidacy. Hepaticojejunostomy with Roux-en-Y bypass is an option if complete resection is not possible. If the patient is not a surgical candidate, palliation can be achieved with an endoscopically placed common bile duct stent, usually a metal stent. If endoscopic stent placement is not successful, a percutaneous transhepatic cholangiography tube can be placed for biliary decompression. Antibiotics are considered in the prebiliary and postbiliary decompression phases to reduce the risk of sepsis.

Management of Pruritus

In cases of obstructive physiology, pruritus may be relieved within 24 to 48 hours of biliary decompression. In other cases, medications may be needed for symptomatic control.[18] Medications options include:(B3)

• Ursodeoxycholic acid: This is recommended in doses of 13 to 15 mg/kg daily to treat the underlying condition in patients with cholestasis due to PBC and the pruritus associated with intrahepatic cholestasis of pregnancy.

• Antihistamines: These may be used for mild symptoms in patients with insomnia resulting from pruritus. They may benefit from the sedating effects.

• Cholestyramine: This bile acid sequestrant is considered first-line therapy for moderate to severe symptoms and is prescribed at a starting dose of 4 g to a maximum dose of 16 g, administered once or twice daily. Maximum dose is achieved by increasing the dose by 4 g daily every 4 weeks. Cholestyramine is best administered before breakfast to enhance the excretion of pruritogens, believed to have been stored in the gallbladder during the overnight fast. Patients should take the minimal effective dose to avoid adverse events, eg, nausea, steatorrhea, and fat-soluble vitamin malabsorption.

• Rifampin: This drug is used if cholestyramine does not relieve pruritus; this has been shown to improve pruritus when administered 150 mg to 300 mg twice daily. Serious adverse events include hepatitis, renal failure, and hemolytic anemia. Therefore, regular monitoring of aminotransferases is recommended.

• Naltrexone: This is an opioid antagonist administered at 12.5 mg to 50 mg daily. The efficacy is thought to be related to the role of endogenous opioids in the pathogenesis of cholestatic pruritus. This should not be prescribed to patients receiving opioid medications and should be used with caution in patients with underlying chronic pain conditions.

• Sertraline: This selective serotonin reuptake inhibitor has shown some efficacy in improving pruritus in small series when administered at 75 to 100 mg daily.

Nonpharmacological treatment options include ultraviolet light and plasmapheresis. These modalities are generally less effective, expensive, and not readily available for routine care of patients with pruritus. Surgical resection of less than 15% of the terminal ileum to prevent enterohepatic circulation (bile salt reabsorption) can be effective in intractable pruritus. This intervention may be reserved for refractory cases. Liver transplantation may be the only effective therapy for intractable cases of pruritus, but this is not a standard indication.

Differential Diagnosis

Differential diagnoses that should be considered when evaluating cholestatic jaundice include:

• Acute liver failure
• Acute hepatitis
• Acute pancreatitis
• Amyloidosis
• Autoimmune hepatitis
• Biliary obstruction
• Cholangitis
• Cholecystitis
• Cirrhosis