Case Presentation:

In our Morning Report at WCH, we discussed a case of a patient presenting with progressive abdominal distension and fatigue. Abnormal skin pigmentation was also a prominent examination finding. Subsequent assessment and investigations were compatible with chronic liver disease and ascites related to undiagnosed, long-standing iron-overload due to hemochromatosis.

Learning Points:

1. Causes of abdominal distension
2. Approach to ascites
3. Investigation abnormalities in the setting of chronic liver disease
4. Management of ascites/chronic liver disease
5. Management of hemochromatosis

Causes of Abdominal Distension:

Approach to Ascites:

1. Hydrostatic Pressure
   

• Think about causes of elevated hydrostatic pressure anatomically, starting with the heart
•  any pathology starting with the heart and working backwards through the venous drainage system can cause elevated hydrostatic pressure at the level of the abdominal capillaries:
  • Left-sided heart failure due to valvular heart disease
  • Right-sided heart failure due to left-sided heart failure, chronic lung disease/OSA
  • Hepatic venous thrombosis (Budd Chiari)
  • Cirrhosis due to many causes
    • Chronic drug/toxicity (acetaminophen, alcohol)
    • Chronic infection (HBV, HCV, TB)
    • Autoimmune liver disease (Autoimmune hepatitis, PBC)
    • Metabolic liver disease (NASH, Wilson’s, alpha-1-antitrypsin deficiency
    • Cancer (primary hepatocellular carcinoma or metastatic disease)
  • Portal veinous thrombosis

2. Oncotic Pressure

• Principle determinant of oncotic pressure is serum albumin
• Causes of hypoalbuminemia:
  • Not taking in (malnutrition)
  • Not producing (chronic liver disease)
  • Losing (renal and GI)
    • Urinalysis,  Protein: Creatinine or albumin: creatinine ratio helps identify renal losses
    • GI losses harder to characterize with basic investigations

3. Capillary Leak

• Flux of fluid between intravascular and interstitial spaces occurs through capillary fenestrations
• The “gaps” in capillary walls are enlarged in certain pathological situations including:
  • Infection
  • Inflammation
  • Cancer (peritoneal carcinomatosis)
  • Trauma/Burns/Sepsis

Investigation Abnormalities in Chronic Liver Disease:

• things to “look for” include:
  • Macrocytic anemia
  • Thrombocytopenia
  • Blood Film abnormalities: target cells, acanthocytes
  • Coagulopathy (elevated INR)
  • Hyponatremia
  • Kidney Dysfunction
  • Low albumin
  • Elevated liver enzymes or markers of cholestasis
  • Specific etiology-related abnormalities:
    • elevated GGT: suggestive of chronic liver disease-related
    • ANA and ASMA +: autoimmune hepatitis
    • AMA +: Primary biliary cirrhosis
    • Low alpha-1-antitrypsin levels: alpha-1-antitrypsin deficiency
    • Low ceruloplasmin: Wilson’s Disease
    • HBV, HCV serologies: viral hepatitis
    • AFP: Hepatocellular carcinoma
    • Elevated Ferritin, TSAT: Hemochromatosis
  • Abdominal Ultrasound:
    • Small, nodular liver
    • Splenomegaly
    • Possibly reversal of flow in portal/hepatic veins
    • Ensure no solitary nodules (HCC)
  • Paracentesis
    • Must send: fluid albumin level, cell count, culture, and cytology
    • Serum Ascites Albumin Gradient (SAAG) helps distinguish the causes of ascites:
      • Low SAAG (<11): Suggestive of capillary leak
        • Explained: albumin is leaking through the capillaries and is equilibrating between the intravascular and interstitial spaces; hence subtracting the difference between the 2 reveals a low/no gradient
        • DDx:
          • Peritoneal carcinomatosis
          • TB
          • Serositis (i.e. SLE)
          • Pancreatitis
      • High SAAG (>11): suggestive of a hydrostatic pressure problem
        • Explained: fluid is getting pushed out by high pressures upstream but albumin is not leaking out because the capillary fenestrations are unaffected
        • DDx: Any of the causes of elevated hydrostatic pressure listed above!

Management of Ascites/Chronic Liver Disease:

1. Dietary considerations
   

   Protein	Daily protein intake 1-1.5 g/kg dry body weight Protein restriction does NOT mitigate risk of encephalopathy Avoiding “fasting state” (which promotes breakdown of protein and associated ammonia production) by having regularly spaced small meals, including in late evening to prevent overnight depletion
   Salt	Restrict <2g/day
   Fluid	Restrict only if Na <120
   Vitamin	Start MVN, Zinc, commonly deficient

2. Selected Exposure considerations:
   

   Alcohol	Avoid
   Analgesia	Avoid NSAIDs (except ASA in patient indicated from a CVD perspective) Limit or avoid opiates (trigger encephalopathy) Acetaminophen ok: <2g/day
   PPI	Unless good indication, cirrhotic patients are at risk of subsequent reinfection (in those hospitalized with an initial infection)
   Herbals/ Naturals	Avoid; many are hepatotoxic
   Statins	Can cause elevated LFTs but can safely be started and continued in cirrhotic patients
   Other Drug Issues	Antiplatelets/anticoagulants: recognize patients are at heightened bleeding risk (low platelets, clotting factor deficiency, varices) so must balance pros/cons Many drugs are liver metabolized and need dose reductions or switching drugs Some drugs are prodrugs that require liver-related activation (i.e. enalapril is a pro-drug) so alternative drug may be optimal (i.e. lisinopril) Bioavailability of some drugs is increased in chronic liver disease (i.e. metoprolol)

3. Blood Pressure Management
   • even with history of HTN, progressively normalizes, then hypotension ensues in setting of chronic liver disease
   • ideally avoid treating HTN when MAP <82 mm Hg (corresponds with 100/73) as this is single variable most associated with reduced probability of survival
   • regarding use of non-selective beta blockers (i.e. nadolol):
     • “window hypothesis” suggests survival increased only within certain clinical window
       • Early cirrhosis, no moderate-large varices, beta blockers do not prevent varices from developing and have adverse effects
       • Window opens when moderate-large varices develop, with or without bleeding, then indicated for primary or secondary prevention
       • Window closes when refractory ascites, HoTN, hepatorenal syndrome, spontaneous bacterial peritonitis, sepsis, or severe alcoholic hepatitis are present
4. Ascites Management:
   • Salt restriction, as above, a mainstay
   • Diuretic Cocktail:
     • Combination of spironolactone and lasix in a 2: 1 ratio
     • Typical starting dose: Spironolactine 100 mg: Lasix 40 mg daily
     • Initially target 0.5-1 kg weight loss/day
   • Diuretic-refractory:
     • Serial paracentesis +/- albumin
     • TIPS
     • Liver transplant
5. Prognostication:
   • 2 major scoring schemes used:
     • MELD-Model for End-Stage Liver Disease
       • initially developed to predict 3 month mortality after TIPS; now used to help prioritize patients for transplant
     • Child-Pugh Classification
       • Scores Range from 5-15
         • Class A (5-6): Compensated cirrhosis
         • Class B (7-9): Significant liver functional compromise
         • Class C (10-15): Decompensated cirrhosis
     • Early referral for/consideration of transplant (extensive work-up needed)
6. Preventative Care/Screening Considerations:
   • Vaccinations: Hepatitis A, B, and influenza
   • Cancer: HCC screening with ultrasound q6 months; AFP may aid in screening
   • OGD to assess for varices

Management of Hemochromatosis:

1. Dietary Considerations:
   • Limit Vitamin C (promotes dietary iron absorption) and iron supplements
   • Avoid raw shellfish/uncooked seafood due to infection risk:
     • Certain bacteria have heightened virulence related to iron
       • Listeria monocytogenes
       • Yersinia enterocolita
       • Vibrio vulnificus
2. Assess for other organ involvement:
   • Pituitary/Adrenal: TSH, LH, FSH, testoserone, DHEAS
   • Thyroid: T3, T4
   • Pancreas: Fasting glucose, HbA1c
   • Joints: XRAYs (especially involved 2nd and 3rd MCPs)
   • Heart: ECG (low voltages), ECHO, etc.
   • Liver Biopsy if:
     • Abnormal liver enzymes
     • Ferritin >1000
     • Possibly: age >40 with other liver disease risk factors
3. Confirm diagnosis with hemochromatosis genetic evaluation
   • 1st degree family members should also be evaluated
4. Phlebotomy
   • Initially 500 cc qweekly/biweekly
   • Replace with saline to avoid HoTN/tacchycardia
   • Target ferritin <50
   • Avoid anemia (alter intervals of phlebotomy if Hb <110)

Final Take-Home Points:

• Diagnostic imaging alone (triphasic abdominal CT) is sufficient to make a diagnosis of hepatocellular carcinoma
• The Reitan trail-making test can be used to evaluate for hepatic encephalopathy. Patients should be able to complete the task in the same number of seconds (or less) as their age.
• Hepatic hydrothorax usually is right-sided and is thought to be due to movement of ascites through a defect in the diaphragm. Chest tubes should be avoided.
• In the differential for clinical jaundice would be carotenemia which also causes a yellow/orange appearance of the skin. It can be differentiated from jaundice owing to the absence of scleral involvement. Carotenemia typically appears at sites with abundant stratum corneum in the skin (i.e. palms/soles) and is usually seen in children where it is dietary-related. Rarely, however, it can also be a manifestation of chronic liver disease.
• Parotid hypertrophy is a regularly cited manifestation of chronic liver disease which has a large differential diagnosis:
  • Acute: EBV, Mumps, CMV, Coxsackie
  • Chronic: HIV, HCV, IgG4 disease, Infiltrative (amyloid, sarcoid, TB), acoholism, Sjogrens, Anorexia/Bulimia

Useful Resources:

• Ge, PS and Runyon, BA. Treatment of Patients with Cirrhosis. NEJM 2016:375:767-777
• AASLD Guidelines for ascites/cirrhosis and hemochromatosis