Cholestatic Jaundice

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.   (A1)

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

• Acute liver failure

• Acute hepatitis

• Acute pancreatitis

• Amyloidosis

• Autoimmune hepatitis

• Biliary obstruction

• Cardiac cirrhosis

• Cholangitis

• Cholecystitis

• Cirrhosis