Cholestasis: Clinical Case and Viva QnA

1. Clinical Case of Cholestasis in Children

A 2-month-old male infant is brought to the pediatric clinic by his parents with concerns of yellowing skin and dark urine for the past week. The infant was born full-term via normal vaginal delivery with no complications during pregnancy or delivery.

History:

• Exclusively breastfed
• No fever or irritability
• Gaining weight adequately
• Stools described as pale and clay-colored for the past 5 days

Physical Examination:

• Weight: 5.2 kg (50th percentile)
• Length: 58 cm (50th percentile)
• Temperature: 37°C
• Jaundice evident on skin and sclera
• Mild hepatomegaly (liver palpable 2 cm below costal margin)
• No splenomegaly

Laboratory Results:

• Total bilirubin: 8.5 mg/dL (Normal: <1.0 mg/dL)
• Direct bilirubin: 5.2 mg/dL (Normal: <0.3 mg/dL)
• ALT: 145 U/L (Normal: <50 U/L)
• AST: 160 U/L (Normal: <40 U/L)
• GGT: 250 U/L (Normal: <204 U/L)
• Alkaline phosphatase: 480 U/L (Normal: <449 U/L)

Further Workup:

• Abdominal ultrasound: No evidence of biliary tract obstruction
• HIDA scan: Non-visualization of the gallbladder or bowel after 24 hours

Diagnosis:

Based on the clinical presentation, laboratory findings, and imaging results, the infant was diagnosed with biliary atresia. The patient was referred for urgent Kasai portoenterostomy.

2. Clinical Presentations of Cholestasis in Children

1. Neonatal Cholestasis (Biliary Atresia)

   • Jaundice persisting beyond 2 weeks of age
   • Dark urine and pale, acholic stools
   • Hepatomegaly
   • Failure to thrive
   • Pruritus (in older infants)

2. Progressive Familial Intrahepatic Cholestasis (PFIC)

   • Chronic cholestasis from early infancy
   • Severe pruritus
   • Growth retardation
   • Jaundice
   • Hepatosplenomegaly

3. Alagille Syndrome

   • Chronic cholestasis
   • Characteristic facies (broad forehead, deep-set eyes, pointed chin)
   • Butterfly vertebrae
   • Peripheral pulmonary stenosis
   • Posterior embryotoxon in the eye

4. Alpha-1 Antitrypsin Deficiency

   • Neonatal cholestasis
   • Prolonged jaundice
   • Hepatomegaly
   • Elevated liver enzymes
   • May present later in childhood with chronic liver disease

5. Choledochal Cyst

   • Intermittent abdominal pain
   • Jaundice
   • Palpable abdominal mass
   • Fever (if complicated by cholangitis)
   • May present with pancreatitis

6. Cystic Fibrosis-associated Liver Disease

   • Neonatal cholestasis
   • Recurrent respiratory infections
   • Failure to thrive
   • Steatorrhea
   • Progressive cirrhosis in some cases

7. Neonatal Hepatitis

   • Jaundice
   • Hepatomegaly
   • Poor feeding
   • Lethargy
   • May have associated viral symptoms (fever, rash)

8. Parenteral Nutrition-Associated Cholestasis

   • Develops in infants on long-term parenteral nutrition
   • Progressive jaundice
   • Hepatomegaly
   • Elevated liver enzymes and bilirubin
   • May progress to liver fibrosis if prolonged

3. Viva Questions and Answers on Cholestasis in Children

25 Viva Questions and Answers on Cholestasis in Children

1. Q: What is the definition of cholestasis?

   A: Cholestasis is defined as a reduction in bile flow due to impaired secretion by hepatocytes or obstruction of bile flow through intra- or extrahepatic bile ducts. It results in the accumulation of bile acids, bilirubin, and other cholephiles in the liver and systemic circulation.

2. Q: What are the key clinical features that suggest cholestasis in a neonate?

   A: Key clinical features include jaundice persisting beyond 2 weeks of age, dark urine, pale or acholic stools, hepatomegaly, and in some cases, failure to thrive. Pruritus may be present in older infants.

3. Q: What is conjugated hyperbilirubinemia and why is it significant in cholestasis?

   A: Conjugated hyperbilirubinemia is defined as a direct bilirubin level >1 mg/dL if the total bilirubin is <5 mg/dL, or >20% of the total bilirubin if it is >5 mg/dL. It is significant because it indicates hepatobiliary dysfunction and is always pathological in neonates and infants.

4. Q: What is the most common cause of neonatal cholestasis?

   A: The most common cause of neonatal cholestasis is biliary atresia, accounting for approximately 25-40% of cases. Other common causes include idiopathic neonatal hepatitis, alpha-1 antitrypsin deficiency, and various metabolic disorders.

5. Q: Describe the pathophysiology of biliary atresia.

   A: Biliary atresia is characterized by progressive inflammatory obliteration of both intrahepatic and extrahepatic bile ducts, leading to bile flow obstruction, cholestasis, and progressive liver fibrosis. The exact etiology is unknown but is thought to involve a combination of genetic predisposition and environmental factors, possibly including viral infections.

6. Q: What is the significance of pale or acholic stools in neonatal cholestasis?

   A: Pale or acholic stools indicate a lack of bile pigments in the intestine, suggesting complete or near-complete biliary obstruction. This finding is particularly concerning for biliary atresia and requires urgent evaluation and intervention.

7. Q: What initial laboratory tests should be ordered when evaluating a child with suspected cholestasis?

   A: Initial laboratory tests should include total and direct bilirubin, ALT, AST, GGT, alkaline phosphatase, albumin, prothrombin time, complete blood count, and glucose. Additional tests may include alpha-1 antitrypsin level, thyroid function tests, and screening for metabolic disorders.

8. Q: How does the HIDA scan help in the diagnosis of biliary atresia?

   A: The HIDA (hepatobiliary iminodiacetic acid) scan assesses bile flow from the liver to the intestine. In biliary atresia, there is typically no visualization of the gallbladder or intestine even after 24 hours, indicating obstruction of bile flow. However, this finding is not specific to biliary atresia and can occur in severe intrahepatic cholestasis as well.

9. Q: What is the Kasai procedure and when is it indicated?

   A: The Kasai procedure, or hepatoportoenterostomy, is a surgical intervention for biliary atresia. It involves removing the obliterated bile ducts and connecting the porta hepatis directly to a loop of jejunum to restore bile flow. It is indicated as soon as possible after the diagnosis of biliary atresia, ideally before 8-10 weeks of age for the best outcomes.

10. Q: What are the three types of Progressive Familial Intrahepatic Cholestasis (PFIC) and how do they differ?

    A: PFIC has three main types: PFIC1 (FIC1 deficiency): Low GGT, defect in FIC1 protein involved in bile acid transport. PFIC2 (BSEP deficiency): Low GGT, defect in bile salt export pump. PFIC3 (MDR3 deficiency): High GGT, defect in phospholipid transporter. PFIC1 and PFIC2 present in infancy with severe pruritus, while PFIC3 may present later in childhood or adolescence.

11. Q: What are the main features of Alagille syndrome?

    A: Alagille syndrome is characterized by: 1. Chronic cholestasis 2. Characteristic facies (broad forehead, deep-set eyes, pointed chin) 3. Butterfly vertebrae 4. Peripheral pulmonary stenosis 5. Posterior embryotoxon in the eye It is caused by mutations in the JAG1 or NOTCH2 genes.

12. Q: How does alpha-1 antitrypsin deficiency cause liver disease?

    A: Alpha-1 antitrypsin deficiency causes liver disease due to the accumulation of misfolded alpha-1 antitrypsin protein in hepatocytes. This accumulation triggers cellular stress responses and can lead to hepatocyte injury and death. Over time, this can progress to chronic liver disease and cirrhosis.

13. Q: What is the role of ursodeoxycholic acid in the management of cholestasis?

    A: Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid that can help manage cholestasis by: 1. Increasing bile flow 2. Displacing toxic bile acids 3. Protecting hepatocytes from bile acid-induced apoptosis 4. Potentially reducing pruritus It is commonly used in various cholestatic conditions, including PFIC and Alagille syndrome.

14. Q: How does cystic fibrosis lead to liver disease?

    A: In cystic fibrosis, mutations in the CFTR gene lead to abnormal chloride transport in biliary epithelial cells. This results in thick, viscous bile that can obstruct bile ducts, leading to focal biliary cirrhosis. Over time, this can progress to multilobular biliary cirrhosis and portal hypertension in some patients.

15. Q: What are the main causes of neonatal hepatitis?

    A: Neonatal hepatitis can be caused by: 1. Viral infections (e.g., CMV, HSV, HIV) 2. Bacterial infections (e.g., sepsis, UTI) 3. Metabolic disorders (e.g., galactosemia, tyrosinemia) 4. Endocrine disorders (e.g., hypopituitarism) 5. Genetic disorders (e.g., Niemann-Pick disease) In many cases, the exact cause remains unknown (idiopathic neonatal hepatitis).

16. Q: How does parenteral nutrition contribute to cholestasis in infants?

    A: Parenteral nutrition-associated cholestasis (PNAC) occurs due to: 1. Lack of enteral stimulation, reducing bile flow 2. Direct toxicity of parenteral nutrition components 3. Altered gut microbiome 4. Potential contaminants in parenteral nutrition solutions 5. Underlying medical conditions necessitating long-term PN Risk factors include prematurity, low birth weight, and duration of PN.

17. Q: What is the significance of fat-soluble vitamin deficiencies in cholestasis?

    A: Fat-soluble vitamin (A, D, E, K) deficiencies are common in cholestasis due to impaired bile flow and fat malabsorption. This can lead to: - Vitamin A: Night blindness, xerophthalmia - Vitamin D: Rickets, osteomalacia - Vitamin E: Neurological symptoms, hemolytic anemia - Vitamin K: Coagulopathy Supplementation is crucial to prevent these complications.

18. Q: How does one differentiate between biliary atresia and neonatal hepatitis clinically?

    A: Differentiating between biliary atresia and neonatal hepatitis can be challenging, but some key features may help: - Biliary atresia: Consistently pale stools, progressive jaundice, often well-appearing infant - Neonatal hepatitis: Variable stool color, fluctuating jaundice, may have systemic symptoms Ultimately, liver biopsy and intraoperative cholangiogram are often necessary for definitive diagnosis.

19. Q: What is the role of genetic testing in the evaluation of pediatric cholestasis?

    A: Genetic testing plays an increasingly important role in diagnosing cholestatic disorders. It can: 1. Confirm diagnoses in conditions like PFIC, Alagille syndrome, and alpha-1 antitrypsin deficiency 2. Identify carriers in families 3. Allow for prenatal diagnosis in subsequent pregnancies 4. Guide treatment decisions and prognosis 5. Identify novel genetic causes of cholestasis

20. Q: Describe the management of pruritus in cholestatic children.

    A: Management of pruritus in cholestatic children includes: 1. Ursodeoxycholic acid: First-line therapy 2. Rifampicin: Second-line, induces hepatic enzymes 3. Cholestyramine: Bile acid sequestrant 4. Naltrexone or naloxone: Opioid antagonists 5. Sertraline: SSRI with antipruritic effects 6. Antihistamines: Limited efficacy but may help with sleep 7. Topical treatments: Emollients, menthol-based creams 8. In severe cases: Consider partial external biliary diversion or liver transplantation

21. Q: What are the indications for liver transplantation in pediatric cholestatic disorders?

    A: Indications for liver transplantation in pediatric cholestatic disorders include: 1. End-stage liver disease with portal hypertension or synthetic dysfunction 2. Recurrent cholangitis in biliary atresia 3. Intractable pruritus significantly affecting quality of life 4. Failure to thrive despite optimal medical management 5. Hepatocellular carcinoma 6. Severe metabolic decompensation in certain inherited disorders

22. Q: How does one manage a child with biliary atresia post-Kasai procedure?

    A: Management of a child with biliary atresia post-Kasai procedure includes: 1. Close monitoring of liver function and nutritional status 2. Fat-soluble vitamin supplementation 3. Ursodeoxycholic acid to promote bile flow 4. Prophylactic antibiotics to prevent cholangitis 5. Aggressive management of complications like ascites or variceal bleeding 6. Optimizing nutrition, often requiring MCT-enriched formulas 7. Consideration for liver transplantation if progressive liver failure develops

23. Q: What is the pathophysiology of pruritus in cholestasis?

    A: The pathophysiology of pruritus in cholestasis is complex and not fully understood. It likely involves: 1. Accumulation of bile acids in the skin 2. Increased opioidergic tone 3. Altered serotonin signaling 4. Lysophosphatidic acid (LPA) accumulation 5. Autotaxin activity 6. Histamine release The exact mechanisms may vary between different cholestatic disorders.

24. Q: How does one diagnose and manage choledochal cysts in children?

    A: Diagnosis of choledochal cysts typically involves: 1. Ultrasound as initial imaging 2. MRCP for detailed biliary anatomy 3. ERCP in selected cases Management includes: 1. Surgical excision of the cyst 2. Roux-en-Y hepaticojejunostomy 3. Long-term follow-up due to risk of cholangiocarcinoma Early surgery is preferred to prevent complications like cholangitis and malignancy.

25. Q: What are the main differences between intrahepatic and extrahepatic causes of cholestasis?

    A: Main differences include: Intrahepatic causes: - Often have associated metabolic or genetic disorders - May have fluctuating jaundice and variable stool color - GGT may be normal or only mildly elevated Extrahepatic causes: - Usually have persistently pale stools - Progressive jaundice - Often have significantly elevated GGT - May have a palpable mass in cases like choledochal cyst

26. Q: How does total parenteral nutrition (TPN) affect liver function in infants?

    A: TPN can affect liver function in infants through: 1. Direct hepatotoxicity of some TPN components 2. Lack of enteral stimulation leading to reduced bile flow 3. Altered gut microbiome 4. Oxidative stress from lipid peroxidation 5. Inflammation and immune activation 6. Potential contaminants in TPN solutions These factors can lead to cholestasis, steatosis, and in severe cases, liver fibrosis.

27. Q: What is the role of nuclear hepatobiliary imaging in the evaluation of neonatal cholestasis?

    A: Nuclear hepatobiliary imaging (e.g., HIDA scan) is used to: 1. Assess bile flow from liver to intestine 2. Help differentiate biliary atresia from other causes of neonatal cholestasis 3. Evaluate gallbladder function In biliary atresia, there's typically no excretion into the intestine even after 24 hours. However, this finding is not specific to biliary atresia and can occur in severe intrahepatic cholestasis as well.

28. Q: Describe the nutritional management of a child with chronic cholestasis.

    A: Nutritional management of a child with chronic cholestasis involves: 1. High-calorie diet (130-150% of normal requirements) 2. Medium-chain triglyceride (MCT) supplementation 3. Fat-soluble vitamin supplementation (A, D, E, K) 4. Adequate protein intake 5. Supplementation of other vitamins and minerals as needed 6. Consideration of nocturnal enteral feeding in severe cases 7. Regular monitoring of nutritional status and growth