Skip to content

Cholestasis: A Comprehensive Overview ๐Ÿฅ

Introduction and Definition ๐Ÿ“‹

Cholestasis represents a pathophysiological state characterized by impaired bile formation or flow, resulting in retention of bile constituents normally excreted into bile. This leads to accumulation of bile acids, bilirubin, and other biliary constituents in blood and tissues1. Clinically, cholestasis manifests as jaundice, pruritus, fatigue, and characteristic laboratory abnormalities including elevated alkaline phosphatase and ฮณ-glutamyl transferase (GGT).

Classification and Etiology ๐Ÿ—‚๏ธ

Cholestasis is broadly classified into two major categories:

Intrahepatic Cholestasis

Results from disorders affecting hepatocytes or intrahepatic bile ducts:

Hepatocellular causes: - Viral hepatitis (especially fibrosing cholestatic hepatitis) - Alcoholic hepatitis - Drug-induced cholestasis - Total parenteral nutrition - Sepsis - Postoperative state2

Bile duct disorders: - Primary biliary cholangitis (PBC) - Primary sclerosing cholangitis (PSC) - Vanishing bile duct syndrome - Progressive familial intrahepatic cholestasis (PFIC) - Benign recurrent intrahepatic cholestasis (BRIC)

Extrahepatic Cholestasis

Results from mechanical obstruction of large bile ducts:

Malignant causes ๐Ÿฆ : - Cholangiocarcinoma - Pancreatic cancer - Gallbladder cancer - Ampullary cancer - Malignant porta hepatis lymphadenopathy

Benign causes: - Choledocholithiasis - Postoperative strictures - Chronic pancreatitis - Parasitic infections (ascariasis) - Mirizzi's syndrome3

Pathophysiology ๐Ÿงฌ

Molecular Mechanisms

Bile formation depends on coordinated function of hepatocellular transporters:

  1. Uptake transporters (basolateral):
  2. NTCP (sodium-taurocholate cotransporting polypeptide)

  3. OATP1B1/1B3 (organic anion transporting polypeptides)

  4. Canalicular exporters:

  5. BSEP (bile salt export pump) - exports bile acids
  6. MRP2 (multidrug resistance-associated protein 2) - exports organic anions
  7. MDR3 (multidrug resistance protein 3) - exports phospholipids4

Consequences of Cholestasis

Retention of bile constituents leads to: - Hepatocellular necrosis (bile acid toxicity) - Pruritus (accumulated pruritogens) - Malabsorption of fat-soluble vitamins (A, D, E, K) - Hyperlipidemia (formation of lipoprotein-X) - Xanthoma formation

Clinical Presentation ๐Ÿฉบ

Cardinal Features

Jaundice ๐Ÿ’› - Visible when bilirubin >2-3 mg/dL - Dark urine (conjugated bilirubinuria) - Pale stools (reduced stercobilin)

Pruritus - Often worst on palms and soles - Exacerbated at night - May precede jaundice - Mechanism involves accumulated pruritogens

Fatigue - Multifactorial etiology - Can be debilitating - Poor correlation with disease severity

Associated Findings

  • Hepatomegaly
  • Steatorrhea (fat malabsorption)
  • Bone disease (osteoporosis/osteomalacia)
  • Hyperpigmentation (chronic cases)
  • Xanthomas and xanthelasmas5

Diagnostic Approach ๐Ÿ”

Laboratory Evaluation

Cholestatic pattern: 

- Alkaline phosphatase โ†‘โ†‘โ†‘ (>4ร— normal)
- GGT โ†‘โ†‘โ†‘ (confirms hepatic origin)
- Conjugated bilirubin โ†‘โ†‘
- ALT/AST โ†‘ (usually <300 IU/L)
- Cholesterol โ†‘ (with appearance of Lp-X)

Additional tests: - PT/INR (vitamin K deficiency) - Fat-soluble vitamin levels - Specific antibodies: - Antimitochondrial antibody (PBC) - p-ANCA (PSC)

Imaging Algorithm ๐Ÿ“Š

  1. Ultrasound (first-line):
  2. Evaluates bile duct dilation
  3. High sensitivity for obstruction

  4. Identifies gallstones

  5. MRCP (if ultrasound equivocal):

  6. Non-invasive cholangiography
  7. Detects strictures, stones

  8. Preferred for PSC evaluation

  9. ERCP (therapeutic intent):

  10. Stone extraction
  11. Stricture dilation

  12. Tissue sampling

  13. Liver biopsy (intrahepatic cholestasis):

  14. Confirms diagnosis
  15. Assesses fibrosis stage
  16. Excludes infiltrative diseases6

Specific Cholestatic Conditions ๐ŸŽฏ

Drug-Induced Cholestasis ๐Ÿ’Š

Pure cholestasis: - Anabolic steroids - Contraceptive steroids - Cyclosporine

Mixed hepatitis-cholestasis: - Amoxicillin-clavulanate - Phenytoin - Sulfonamides

Chronic cholestasis: - Chlorpromazine - Prochlorperazine

Management involves immediate drug discontinuation and supportive care.

Primary Biliary Cholangitis (PBC)

  • Autoimmune destruction of interlobular bile ducts
  • 95% AMA-positive
  • Female predominance (9:1)
  • Treatment: Ursodeoxycholic acid (UDCA) first-line

Intrahepatic Cholestasis of Pregnancy (ICP) ๐Ÿคฐ

  • Third trimester onset
  • Severe pruritus
  • Elevated bile acids (>10 ฮผmol/L)
  • Risk of stillbirth
  • Treatment: UDCA, delivery by 37 weeks7

Progressive Familial Intrahepatic Cholestasis (PFIC)

Three main types based on genetic defects: - PFIC1 (ATP8B1) - normal GGT - PFIC2 (ABCB11/BSEP) - normal GGT - PFIC3 (ABCB4/MDR3) - elevated GGT

Benign Recurrent Intrahepatic Cholestasis (BRIC)

  • Episodic cholestasis
  • Complete resolution between episodes
  • No progression to cirrhosis
  • Mutations in ATP8B1 or ABCB11

Management Strategies ๐Ÿ’Š

General Measures

Pruritus management: 1. First-line: Cholestyramine (4-16 g/day) 2. Second-line: Rifampin (150-300 mg bid) 3. Third-line: Naltrexone (50 mg/day) 4. Fourth-line: Sertraline (75-100 mg/day) 5. Severe cases: Plasmapheresis, MARS8

Nutritional support ๐Ÿฅ—: - Fat-soluble vitamin supplementation: - Vitamin A: 10,000-50,000 IU/day - Vitamin D: 800-1200 IU/day - Vitamin E: 400-800 IU/day - Vitamin K: 10 mg weekly

Bone disease prevention: - Calcium supplementation (1500 mg/day) - Bisphosphonates if osteoporosis - Weight-bearing exercise

Specific Therapies

Ursodeoxycholic acid (UDCA): - Mechanism: Hydrophilic bile acid replacement - Dose: 13-15 mg/kg/day - Indicated for PBC, ICP, some drug-induced cases

Obeticholic acid: - FXR agonist - Second-line for PBC - Dose: 5-10 mg/day - Monitor for pruritus exacerbation

Endoscopic/Surgical interventions: - ERCP for stone extraction - Biliary stenting for malignant obstruction - Surgical resection when appropriate

Complications and Prognosis ๐Ÿ”ฎ

Acute Complications

  • Cholangitis (fever, jaundice, RUQ pain)
  • Biliary cirrhosis
  • Portal hypertension
  • Hepatocellular carcinoma (chronic PBC/PSC)

Long-term Sequelae

  • Metabolic bone disease
  • Peripheral neuropathy (vitamin E deficiency)
  • Night blindness (vitamin A deficiency)
  • Coagulopathy (vitamin K deficiency)

Prognostic Factors

Poor prognosis associated with: - Persistent hyperbilirubinemia (>6 mg/dL) - Refractory pruritus - Progressive synthetic dysfunction - Development of cirrhosis

Liver Transplantation Considerations ๐Ÿฅ

Indications for transplant evaluation: - Intractable pruritus - Recurrent bacterial cholangitis - Progressive liver failure - Hepatocellular carcinoma (Milan criteria)

Excellent outcomes for cholestatic diseases: - 5-year survival >80% for PBC - Recurrence possible (especially PSC)

Conclusion ๐Ÿ“

Cholestasis represents a complex syndrome requiring systematic evaluation to distinguish intrahepatic from extrahepatic causes. The diagnostic approach begins with recognition of the cholestatic pattern of liver tests, followed by appropriate imaging to exclude biliary obstruction. Management focuses on treating the underlying cause when possible, managing symptoms (particularly pruritus), preventing complications through nutritional support, and timely referral for liver transplantation when indicated. Understanding the molecular basis of cholestasis has led to targeted therapies like obeticholic acid, with promising agents in development. Early recognition and appropriate management of cholestasis can significantly improve patient outcomes and quality of life.

  1. Harrison's Principles of Internal Medicine, 21st Edition, Chapter 49: Jaundice ↩

  2. Table 49-3: Cholestatic Conditions That May Produce Jaundice, Harrison's Principles of Internal Medicine ↩

  3. Chapter 337: Diseases of the Gallbladder and Bile Ducts, Harrison's Principles of Internal Medicine ↩

  4. Figure 338-1: Hepatocyte bile acid transporters, Harrison's Principles of Internal Medicine ↩

  5. Lindor KD et al: Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology 69:394, 2019 ↩

  6. Figure 49-1: Evaluation of the patient with jaundice, Harrison's Principles of Internal Medicine ↩

  7. Ovadia C et al: Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers. Lancet 393:899, 2019 ↩

  8. Kremer AE et al: Pathogenesis and management of pruritus in PBC and PSC. Dig Dis 33:164, 2015 ↩