Jaundice, ascites, and encephalopathy Flashcards
Causes of jaundice
Pre-hepatic
- Gilbert’s syndrome
- Hemolysis
- Hematoma
Hepatic
- Tumour infiltration
- Viral hepatitis (may become reactivated while on chemo or immunosuppressive therapy e.g. dex)
- Drug toxicity (acetaminophen, alcohol)
- Cholestasis (drugs, septicemia)
- GVHD
- Venous outflow block (severe heart failure, budd chiari)
Post-hepatic
- Malignant (pancreatic ca, cholangioca, lymphadenopathy
- Gallbladder/bile duct issues (gallstones, chronic pancreatitis, biliary stricture)
Gilbert’s syndrome
- Inherited disorder resulting in a deficiency of an enzyme normally used to break down bilirubin in the liver, which results in more unconjugated bilirubin circulating
- Mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or hemolysis
- Elevated bilirubin levels in response to stresses (fasting, comorbidity, infection, treatment for malignancy)
- May be more vulnerable to toxic side effects with certain chemotherapies
Viral hepatitis in palliative care
- Watch for reactivation of infection related to use of corticosteroids or cytotoxic regimens!
Drug-induced liver disease
- May be both hepatocellular (death of hepatocytes) and cholestatic
Hepatocellular reactions
- Allopurinol
- Herbal remedies
- Halothane
- Minocycline
- Phenytoin
Cholestatic/mixed reactions
- Amox/clav
- Chlorpromazine
- Levomepromazine
- Erythromycin
- TCAs
- Fluoxetine
- Acetylcholinesterase inhibitors
- Enzyme levels typically return to normal after withdrawal of the offending agent (50% by 2 weeks, normalisation by 4 weeks), though cholestatic injury may be more chronic
- Little evidence of increased risk in drug-related hepatotoxicity in patients with pre-existing disease, though slowed metabolism puts them at higher risk of systemic drug toxicity
Pathophysiology of sepsis and jaundice
- Cholestatic, non-obstructive jaundice may occur in sepsis or shock
- Cholestasis due to hypotension, low hepatic blood flow
- Direct inhibition of bile secretion by endotoxin and inflammatory cytokines
Pathophysiology of cardiac failure and the liver
- Rare presentation of CHF, but altered liver function common in advanced CHF
- Due to sinusoidal congestion (results in cholestatic picture with elevated ALP, GGT). Most pronounced in TR.
- Significant hypotension may also result in ischemic hepatitis with very high enzymes (‘shock liver’)
Pathophysiology of Budd-chiari, associations and tx
- Jaundice due to venous occlusion of the hepatic vein
- May be rapid onset or more chronic
- Typical presentation with abdo pain, ascites, hepatomegaly, signs of GI bleeding
Associated with a hypercoagulable state:
- Myeloproliferative disorders
- Polycythemia rubra vera
- Essential thrombocytosis
- Malignancy
Management:
- Correct underlying disorder if possible
- Anticoags, assuming no contraindications (varices!!!!)
- If symptomatic, consult for angiography, stenting, thrombolysis, TIPS
Etiology of obstructive jaundice
- Obstruction of the biliary tract at any point from within the liver to the ambulla of vater
- Gallstones
- Pancreatic ca
- Cholangio ca
- Metastatic ca
- HCC
Note that malignant obstructions are not necessarily painless
Symptoms related to jaundice
- Pruritis
- Nausea
- Indigestion
- Sleep impairment
- Encephalopathy
Workup of jaundice
History PE - Signs of portal hypertension - Intra abdo malignancy - HE (orientation, asterixis)
Labs
- LFTs, INR, CBC (infective cholangitis)
Significance of isolated ALP
- Isolated elevation unusual, may reflect bone disease
Clinical chacteristics of hemolytic jaundice (presentation, LFTs, US findings)
Presentation
- Asymptomatic or backache, arthralgia
- Splenomegaly
LFTs
- Bili <100
Normal ALT, ALP, INR
US
- no dilated bile ducts
Clinical characteristics of hepatocellular jaundice (presentation, LFTs, US findings)
Presentation
- N/V, anorexia, pyrexia
- Tender hepatomegaly
LFTs
- Bili variable
- ALT >5x
- ALP 2-3x
- elevated INR (not corrected by vit K)
US
- no dilated bile ducts
Clinical characteristics of intrahepatic cholestasis (presentation, LFTs, US findings)
Presentation
- Deep jaundice
- Dark urine, light stools
- Pruritis
- Tender hepatomegaly
LFTs
- Bili variable, but may be >500
- 2-5x ALT
- 3-5x ALP
- long INR, may be corrected by Vit K (depending on hepatocellular disease)
US
- no dilated bile ducts
Clinical characteristics of post hepatic cholestasis/obstructive jaundice (presentation, LFTs, US findings)
Presentation
- Deep jaundice
- Dark urine, light stools
- Pruritis, cholangitis
- Biliary cholic
- Hepatomegaly, palpable gallbladder
LFTs
- Bili < 500
- ALT 2-5x
- ALP 3-5x
- elevated INR (corrects with vit K)
US
- Dilated bile ducts
How to differentiatel intrahepatic cholestasis from post hepatic cholestasis
In post-hepatic cholestasis, more likely to have palpable gall bladder, INR correctable with Vit K (impaired intestinal absorption of fat soluble vitamins rather than hepatocellular disease), and dilated bile ducts on US
Imaging for jaundice
US
- Cheap and bedside
- Useful for detecting biliary duct dilatation, but limited in obese patients
CT
- can detect and characterise smaller lesions, stage disease
MRCP
- Differentiate benign versus malignant lesions
- Avoids risks associated wtih ERCP
ERCP
- Allows for imaging, cytology, and dilatation/stent insertion if drainage of the biliary system is required
- Risks include cholangitis, bleeding, bile duct leakage, acute pancreatitis
Management of jaundice
- Chemo for sensitive malignancies
- Biliary drainage procedures may provide rapid relief of pruritis, pain, nausea, anorexia, and QOL
Biliary drainage procedures
ERCP with stent
- stents inserted endoscopically, if at the low CBD
- Failure rate 30-40% plastic stents, 10-15% with metallic
- Higher rates of cholangitis with plastic stents
- If stents occlude, can be replaced (plastic) or have patency restored (metallic)
Percutaneous transhepatic biliary drainage
- Used if level of biliary obstruction is high (proximal to common bile duct) or there is distorted anatomy (prev surgery, local tumour)
- Also second line if ERCP fails
Presentation of cholestatic pruritis
- Itch does not tend to correlate with serum bilirubin levels or stage of chronic liver disease
- Typically starts on palms and soles before becoming more generalised
- Circadian rhythm, worst between 1200 and 1800 hours
Pathophysiology of pruritis in jaundice
- Bile acid accumulation may be pruritogenic (however pruritis does not correlate with bilirubin levels)
- May be due to central neural mechanisms from alterations in endogenous opioids, serotonin, and GABA
Opioid system
- Endogenous opioid levels are elevated in patients with CLD
- Activation of central/peripheral kappa opoid receptors may inhibit itch
- Activation of mu-receptors may contribute to itch (antagonised by naloxone)
Serotoninergic system
- Thought to be involved due to close links between serotonergic and opioidergic transmission systems
Lysophosphatidic acid and autotaxin
- High levels of lysophosphatidic acid in the serum of individuals with cholestatic itch, with levels correlating to severity
- Autotaxin is an enzyme involved in the production of active lysophosphatidic acid
Management of Cholestatic pruritis:
Mild
- Consider emollients, warm baths
- May try antihistamines at night, but not likely to be very effective
Moderate to severe:
- Bile acid sequestrant (cholestyramine, TDD 4-16g)
- If ineffective, switch to rifampin 150-300mg PO BID (reduces autotaxin expression)
If ineffective:
- naltrexone 12.5 - 50mg PO daily (note cannot give if patients is on opioid tx or in active liver failure)
- sertraline 75mg PO daily
Non-pharmacologic management of pruritis
- Keep fingernails cut short and wear cotten gloves at night to reduce skin damage
Unclear evidence:
- Topical emollients
- Stay cool, lessen sweating
Malignancies most commonly associated with ascites
- Ovarian CA (most common)
- Breast
- Colonic CA
- Gastric ca
- Pancreatic CA
- CUP
Prognostication with ascites
- Usually an indicator of advanced disease
In ovarian CA, longer mean survival from the time of development when compared to other cancers as it comes on with relatively early stage CA and can be treated with chemo
Symptoms related to ascites
- Intra abdo pressure
- Abdominal discomfort
- Dyspnea
- Anorexia
- Reflux
- Poor mobility
- Insomnia due to discomfort
- N/V
- Early satiety
- Impacts on body image
Pathophys
Transudative (Cirrhosis, Budd-Chiari, hepatic tumours)
- Portal hypertension
- Results in increased venous pressure with fluid leaking into the peritoneum, with renin secretion by the kidneys and
sodium/fluid retention
Exudative
- Peritoneal tumour bed is vascular with high permeability
- Normal microvessels may become more permeable due to the malignancy driving production of inflammatory cytokines
Differentiate using SAAG
(serum albumin) - (ascitic albumin).
If > 11, due to portal hypertension (cirrhosis, heart failure, budd chiari, etc.) and more likely to be diuretic responsive
If < 11, exudative (peritoneal malignancy, TB, pancreatitis, etc.)
How to calculate/interpret SAAG
Differentiate transudative vs exudative ascites using SAAG
(serum albumin) - (ascitic albumin).
If > 11, due to portal hypertension (cirrhosis, heart failure, budd chiari, etc.) and more likely to be diuretic responsive
If < 11, exudative (peritoneal malignancy, TB, pancreatitis, etc.)
Pathophysiology of chylous ascites
Complication of retroperitoneal tumour spread or its treatment
Occurs due to damage to lymphatic vessels or obstruction of lymphatic flow through lymph nodes or the pancreas
Diagnosis of ascites
Physical exam
When in doubt, US can detect as little as 100 ml of ascitic fluid
Management of malignant ascites (medical TX)
- Always exclude other potential causes (e.g. CHF, cirrhosis, nephrotic syndrome, TB, pancreatitis)
- Cytotoxic therapy
- Consider specific antitumour therapy, especially in patients with known ovarian or breast CA that may benefit greatly
- Chylous ascites may benefit from chemo as well
- Diuretic therapy
- Consider a trial if the SAAG is high or patient has portal HTN, though the role of diuretics in malignant ascites is controversial
- Treat with mineralocorticoid receptor antagonist with Loop (e.g. spironolactone 100mg PO qdaily + 40mg Lasix. Maintain ratio and titrate upwards. Note that this can trigger HE in patients with limited residual hepatic function!
Paracentesis for malignant ascites
- Provides quick symptomatic relief and may bridge patients to effective relief from diuretics
- As per cochrane review, no evidence for speficic methods around length of time to keep the drain in place, use of albumin, clamping, or vitals after drainage.
For frail patients, remove `1-2 L over 30 mins (most significant symptom relief with first 1-2 L).
Otherwise, patients can often tolerate up to 5 L without issue.
Patients who are particularly prone to hypervolemia with paracentesis
- No peripheral edema
- High SAAG (transudative) but not responding to diuretics
If hypotension develops, can consider IV infusion of albumin
When to insert a peritoneal drain
- Patients with malignant ascites not undergoing any type of cytotoxic therapy (likely to reaccumulate within a few days)
- Allows repeated paracentesis from home.
Risks of paracentesis
- Bowel perforation
- Peritonitis
- Localised cellulitis
- Leakage
- Electrolyte shifts
- Bleeding
- Risk of hepatic failure and encephalopathy if severe hepatic compromise
Anecdotally:
- fatigue
- hyponatremia and hypoalbuminemia over time
Peritoneovenous Shunt (PV Shunt) (placement, risks, contrainducations, best outcomes)
- Shunt designed to allow drainage of ascites into the central venous system through the internal jugular or femoral veins
- Placed surgically, laparoscopically, or percutaneously
Risks:
- shunt occlusion
- DIC
- fluid overload
- VTE
- tumour seeding (though not felt to be clinically significant)
Contraindications:
- hemorrhagic ascites
- High ascitic protein content
- loculated ascites
- portal HTN
- renal or cardiac failure
- bleeding disorder
Best outcomes appear to be in patients with normal renal function and tumours of non-GI primary origin
May be worth considering in patients with gyne malignancies given long survival
Hepatic encephalopathy (definition, pathophys
- Neuropsych disturbance as a consequence of progressive liver disease with cirrhosis
- Characterised by abnormal cognitive and motor function as well as psychiatric disturbances
May be due to chronic liver disease or in some cases, malignancy with massive infiltration by a primary or metastatic tumour (though usually the prognosis is in the range of days)
- Sign of decompensation and related to the development of significant portosystemic venous shunting (through collateral or TIPS procedure) or damaged hepatocytes unable to metabolise ammonia
Prognosis is significantly worse after first episode of acute encephalopathy in CLD and shoulkd trigger transplant w/u
Cause of HE
- Ammonia build up (generated in small intestine by bacterial activity)
- Normally transported by the portal vein to the liver where it is metabolised and excreted
- Impaired due to either portosystemic shunting (collaterals) or hepatocyte dysfunction
- Ammonia, rather than be excreted, then accumulates in the systemic circulation and cross the blood brain barrier
- Results in increased GABA activity and cerebral edema due to osmotic pressure in astrocytes
Precipitants of HE in liver disease
- EtOH
- Infection
- Sedating drus
- Dehydration
- Constipation
- Anemia
- GI bleeding
Diagnosis of HE
- Diagnosis of exclusion
- Rule out CVA and space-occupying brain lesion
- Check for other causes of metabolic encephalopathy (uremia, etc.)
- Worth getting a blood ammonia level
Clinical signs:
- Fetor hepaticus
- Asterixis
- Jaundice
- Extrapyramidal signs (tremor, bradykinesia, cog wheel rigidity, shuffling gait)
West Haven criteria for HE
Stage 0
- Impairment only noted on psychomotor testing
- No asterixis
Stage I
- Mild lack of awareness and shortened attention span
- Altered sleep pattern
- Mild asterixis or tremor
Stage 2
- Lethargy, disorientation, inappropriate behaviour
- Slurred speech
- Obvious asterixis
Stage 3
- Somnolent but rousable
- Disorientation
- Bizarre behaviour
- Asterixis absent, high muscle tone and hyperreflexia
Stage 4
- Coma
- Decerebrate posturing
Management of HE
- Diet
- High protein diet may in the short term worsen HE, but in the long term protein restriction can aggravate ascites and worse catabolism
- Optimally, diet with vegetable protein
- Consider referral to nutrition - Disaccharides
- Lactulose will be preferentially consumed by intestinal bacteria, competitively reducing ammonia production. Also increases frequency of BMs and excretion of potential toxins
- Titrate dose to target 2-3 BMs per day
- Weak evidence as per cochrane - Antibiotics
- Rifaximin to reduce urease-producing bacteria in the gut
- Poorly absorbed PO and demonstrates effective reduction in ammonia
- Used if HE is inadequately managed with lactulose (in addition to lactulose) - Ensure euvolemia as dehdration may compound the issue.
Acute management of HE
- Identify and treat underlying cause
- Tap for SBP, CBC, lytes, ammonia, Cr, CT head for other causes, CXR for PNA, pan culture
- Check recent meds, any intoxication
- History for GI bleeding, constipation - Lower blood ammonia
- Start lactulose and titrate to 2-3 BMs per day
- In unconscious patient, may need to do lactulose enemas - If no improvement in 48 hrs, start rifaximin PO (in addition to lactulose)
