8.4 (10.4) Jaundice, ascites, and encephalopathy

Question 1

List THREE categories of unconjugated hyperbili causes and TWO example of each.

Answer 1

◆ Bili overproduction
- Hemolysis
(e.g. sickle cell, autoimmune hemolytic anemia, hereditary spherocytosis, TTP/HUS)
- Ineffective erythropoiesis
(e.g. severe iron def anemia, thalassemia, megaloblastic & sideroblastic anemia, erythropoietic porphyria, erythroleukemia)
- Hematoma reabsorption
- Too much transfusions

◆ Poor liver uptake
- CHF
- Portosystemic shunt

◆ Impaired conjugation by liver
- Gilbert’s syndrome: inherited d/o dec in bili-UGT activity
- Crigler-Najjar syndrome
- Rotor syndrome

Box 8.4.1

Question 2

List THREE top causes of hepatic jaundice worldwide + THREE other causes

Answer 2

◆ Top 3 causes worldwide:
- viral hepatitis (esp hep B and C)
- ETOH liver disease
- non alcoholic fatty liver disease (NAFLD)

◆ Other causes (DIMS)
- drugs: immunotherapy, tylenol, nsaid, abx, accutane, herbs
- infection: septicemia (bacterial, viral)
- metabolic: parenteral nutrition
- structural: tumor infiltration, congestive hepatopathy, hypotension (infarct, severe valvular dz), Budd–Chiari syndrome (aka hepatic venous outflow obstruction)

Question 3

List TWO malignant and TWO benign causes of obstructive jaundice. Which type of bilirubin is elevated?

Answer 3

◆ Malignant:
- carcinoma of the head of the pancreas
- cholangiocarcinoma
- mets to the liver

◆ Benign:
- gallstones (16% of obs jaundice)
- pancreatitis
- parasitic infections
- primary sclerosing cholangitis
- stricture post invasive procedure

Both conjugated and unconjugated inc - but conjugated higher

Question 4

Obstructive jaundice - from where to where can be obstructed?

Answer 4

Any point with in the liver -> ampulla of Vater

Question 5

List three medications that (other than tylenol) are associated with idiosyncratic reactions causing liver injury and hepatic jaundice.

Answer 5

◆ antibiotic (amox clav, flucloxacillin, cipro)

◆ anti-inflamatory (NSAIDs)

◆ immune checkpoint inhibitors (eg. ipilimumab, pembrolizumab, nivolumab)

◆ herbs

Question 6

Initial bloodwork for jaundice

Answer 6

◆ CBC (plt)
◆ Total bili, unconjugated and conjugated
◆ LFTs
◆ Liver function: albumin, INR/PT

FS: complications
- Ammonia (hep enceph)
- e7 (Hepatorenal)

Question 7

List four imaging studies that can be done for assessment of jaundice.

Answer 7

◆ Ultrasound (transcutaneous)
- 1st imaging choice in the pt w/ jaundice.

◆ Endoscopic ultrasonography (EUS)
- more sens for pancreatic & ampullary cancers

◆ Magnetic resonance cholangiopancreatography (MRCP)
- same accuracy as direct cholangiography w/ no cannulation risk

◆ Endoscopic retrograde cholangiopancreatography (ERCP)

◆ Computed tomography w/ contrast
- better imaging than percutaneous US of liver

Question 8

What is Budd-Chiari syndrome?

For patients with appropriate goals of care, what are TWO interventions used to treat acute Budd-Chiari syndrome

Answer 8

Occlusion of the hepatic veins
- Primary = Thrombus
- Secondary = Tumor

◆ Transjugular intrahepatic portosystemic shunt (TIPS)
- shunt placement to connect portal vein and hepatic vein
Sup mesenteric vein + splenic vein + gastric vein -> portal vein -> liver -> hepatic vein -> IVC -> heart

◆ Hepatic vein stent

Question 9

Name biliary drainage procedures

Answer 9

◆ Biliary drains (External vs Internal/External)

• Surgical bypass - surgeon
• endoscopic (ERCP) - GI
• percutaneous (PTC -percutaneous transhepatic cholangiogram) - IR

FS: ERCP most common

Question 10

In what TWO situations would a PTC drain be preferable to ERCP stenting in setting of obstructive jaundice

Answer 10

◆ high bile duct obstruction

◆ distorted duodenal anatomy
- due to previous surgery or presence of local tumour

Question 11

What is the correlation between serum bilirubin levels and subjective experience of pruritus? What is better associated?

Answer 11

◆ No correlation to serum bili or stage of liver dz

◆ Associated with circadian rhythm
- seems to be worse between 1200-1800

Question 12

Chronic cholestasis can lead to difficulties in absorbing certain vitamins - which ones? What is one complication of this?

Answer 12

◆ Fat soluble - ADEK
- vitamin K def causes inc INR -> inc risk bleeding

Question 13

Mechanism of cholestasis induced pruritis

Answer 13

1) Inc circulating bile acids & puritogens

2) Increased autotaxin

3a) Stimulating peripheral itch receptors within skin
and/or
3b) Central neural mech resulting in alterations in NTs (opioids, serotonin, GABA)

FS:

• Bile is excreted into the small intestine to help solubilize fat and VIT ADEK
• Majority is reabsorbed in ileum into portal vein -> liver

Bile = cholesterol + bile acid (bile salt) + bilirubin

Question 14

Name three ways rifampin is proposed to relieve pruritus

Answer 14

◆ Liver: Inhibition of bile acid uptake by hepatocytes*

◆ Liver: Hepatic enzyme inducer (increase metabolism of pruritogens)*

◆ Reduction in circulating levels of autotaxin

◆ Gut: Alteration of bowel flora (decreasing re-uptake of bile acids and pruritogens)*

◆ Central opioid antagonism

Question 15

List four non pharm interventions for pruritus

Answer 15

◆ Topical emollients

◆ environmental measures to cool and lessen sweating

◆ keeping finger nails cut short

◆ wearing cotton gloves at night to lessen damage to the skin through scratching

Question 16

Outline FIVE mechanisms by which cancer causes malignant ascites

Answer 16

◆ Peritoneal carcinomatosis (53%)

◆ Massive liver mets causing portal hypertension
◆ Two of the above causes in combo
◆ Budd chiari syndrome due to cancer occluding hepatic veins
◆ HCC + cirrhosis
◆ Chylous ascites due to malignancy

FS:
- Exudative: Peritoneal carcinomatosis
- Transudative: Portal HTN due to Budd Chiari syndrome, cirrhosis, liver mets (3)
- Chylous ascites

Question 17

What is SAAG, what does it indirectly measure? What does a high SAAG vs low SAAG indicate?

Answer 17

◆Serum to ascitic albumin gradient
- measures portal hypertension

◆ High SAAG (>11mg/L) = portal hypertension -> transudative ascites
(e.g. cirrhosis, BUDD chiari syndrome, alcoholic hepatitis, massive liver mets, portal vein thrombosis)

◆ Low SAAG = exudative ascites
(malignancy like peritoneal carcinomatosis, infection, inflammation)

Question 18

What is chylous ascites? How does it happen

Answer 18

◆ TRI-GLYCERIDE rich ascites as a complication of:

• retroperitoneal tumour spread or its treatment –>
• damage to lymphatic vessels / obstruction of lymphatic flow through lymph nodes or pancreas

Question 19

How to tx chylous ascites due to cancer ? Name 3 methods

Answer 19

◆ Chemotherapy
◆ Statin
◆ TPN

Question 20

How does the prognosis after the first presentation of malignant ascites in ovarian cancer differ from other cancers?

Answer 20

◆ Have a longer mean survival from the time of development of ascites when compared to those with other malignancies

Question 21

Name the TWO mainstay txs of ascites of non-malignant origin

Answer 21

◆ Diuretic
◆ Na restriction

Question 22

What diagnostic test may indicate that a patient with malignant ascites may respond to diuretics? What two diuretics are reasonable to try (what ratio):

Answer 22

◆ High SAAG (>11mg/L) and raised plasma renin

◆ Spironolactone 50mg to furosemide 20mg daily
(max 400mg:160mg)

Question 23

A patient with malignant ascites and a SAAG of 4 has a paracentesis with 5L of fluid removal. What features would make you consider providing IV fluid replacement?

Answer 23

◆ Hypotensive (decrease BP)

◆ Severe renal impairment (decrease GFR)

◆ Dehydration

Question 24

List THREE complications of paracentesis

Answer 24

◆ Leakage

◆ Bowel perforation

◆ Peritonitis

◆ Localized cellulitis at the drainage site

Question 25

What subset of patients with malignant ascites may be prone to hypovolemia following large-volume paracentesis?

Answer 25

◆ Without peripheral edema
or
◆ High SAAG + no diuretic response

Question 26

Procedure to consider for cirrhotic ascites

Answer 26

◆ Transjugular intrahepatic portosystemic shunt (TIPS) - the pressure inside the portal veins is decompressed into the systemic circulation.

Question 27

List FIVE biochemical indicators that indicate a patient presenting with a first episode of hepatic encephalopathy has a worse prognosis than baseline

Answer 27

Low albumin, high bili, high prothrombin activity, high ALP

High potassium, high urea

Not in 6th ed.

FS: think liver + renal

Question 28

Pathophysiology of hepatic encephalopathy

Answer 28

◆ Inc levels of ammonia in the sys circulation come principally from:
- portosystemic shunting
- reduction in the processing capacity of the liver
- dec muscle mass and renal dysfunction further contribute to hyperammonaemia, as these organs have the capacity to break down ammonia as well

◆ In the brain ammonia:
- directly inhibits both excitatory and inhibitory postsynaptic potentials
- disrupts synthesis of neurotransmitters
- causes an increase in production of reactive O & N species
- leads to inc intracellular osmolarity with edema

◆ Intestinal bacteria produce other potential central neurotoxins such as benzodiazepine-like compounds, mercaptans, phenols, and short- and medium-chain fatty acids
- all found in relatively high levels in individuals with chronic liver disease and may contribute to HE.

WP: too much detail?

FS:
- Gut produce ammonia -> systemic circulation
- Liver disease -> portosystemic shunt (blood away from liver) -> ammonia cannot be converted in liver to urea (which is cleared renally)
- Increased ammonia in systemic circulation -> brain -> HE

Question 29

A patient presents with hepatic encephalopathy. List FOUR precipitants that you need to consider as you create a tx plan for this patient

Answer 29

◆ Dehydration, uremia
◆ Metabolic derangements (low K, low glucose)

◆ Sedation
- Drugs: benzodiazepines, opioids, alcohol and other sedatives
- Infection
- Anemia/GI bleed
- Hypoxia

◆ Constipation

FS: think DIMS for delirium

Question 30

What is the American Association for the Study of Liver Disease and the European Association for the Study of the Liver classification of HE stage 0 & 1?

Answer 30

◆ Stage 0:
- lack of detectable changes in personality or behaviour
- min changes in memory, concentration, intellectual function, and coordination
- asterixis is absent

◆ Stage 1:
- trivial lack of awareness w/ a dec attention span.
- hypersomnia, insomnia, or inversion of sleep pattern are classic features of this stage
- patients may complain of euphoria, depression, irritability, and mild confusion
- there is slowing in their ability to perform mental tasks, particularly addition and subtraction.
- asterixis may be detected

Question 31

What is the American Association for the Study of Liver Disease and the European Association for the Study of the Liver classification of HE stage 2?

Answer 31

◆ Stage 2:
- lethargy, drowsiness, or apathy develops.
- there may be inappropriate behaviour reported by those close to the patient.
- slurred speech, gross deficits in ability to perform mental tasks
- obvious personality changes
- intermittent disorientation can be seen (particularly regarding time
- asterixis is obvious and spontaneous

Question 32

What is the American Association for the Study of Liver Disease and the European Association for the Study of the Liver classification of HE stage 3?

Answer 32

◆ Stage 3:
- patients are somnolent but can be aroused
- they are unable to perform mental tasks
- have gross disorientation regarding time and place.
- have marked confusion, associated with amnesia, occasional fits of rage, and often incomprehensible speech.
- Muscle rigidity, clonus, and hyperreflexia have replaced asterixis on physical examination.

Question 33

What is the American Association for the Study of Liver Disease and the European Association for the Study of the Liver classification of HE stage 4?

Answer 33

◆ Stage 4:
- patients are comatose with or without response to painful stimuli
- decerebrate posturing may be seen.

FS: summary of five stages

Stage 0
- LOC - normal
- Cognition - mild changes
- Exam - normal

Stage 1
- LOC - hyper/insomnia
- Cognition - slow
- Exam - May have asterixis

Stage 2
- LOC - lethargic
- Cognition - grossly slow, intermittent disorientation
- Exam - Obvious asterixis

Stage 3
- LOC - drowsy but rousable
- Cognition - very disoriented
- Exam - Myoclonus, rigid, hyper-reflexia

Stage 4
- LOC - comatose
- Cognition - comatose
- Exam - decerebrate

Question 34

How is covert encephalopathy (stage 0+1) identified?

Answer 34

◆ Specific neuropsych testing - number connector test, block design test, digit symbol test

Question 35

Management approach of hepatic encephalopathy

Answer 35

◆ Environmental support (like in delirium)
◆ Family and caregiver education/support
◆ Treat precipitants
◆ Hydration
◆ Lactulose 10-30 mL/day w/ titration to 2-4 soft stools per day (oral, NG ,rectal)
◆ ABx to reduce urease producing bacteria in intestine
- metronydazole, ampicilin, rifaximin

FS-
- Lactulose + Rifaximin/flagyl/ampicilin
- Hydration
- Management of delirium (source, symptoms)
- Educate

Question 36

A patient with hepatic encephalopathy is placed on lactulose. An order is written for 45mL of lactulose q3h. The patient is having very frequent loose BMs. The hepatic encephalopathy appears to be getting worse.

A delirium work up is done that shows sodium of 155.

What will do you? Why?

Answer 36

◆ The maintenance of circulating blood volume by correction of dehydration is important to maintain adequate renal excretion of ammonia

◆ Give fluids, hold lactulose - goal is 2-3 loose BMs per day

Question 37

A patient with hepatic encephalopathy is placed on lactulose. An order is written for 30mL of lactulose TID. The patient is having 2-3 loose BMs per day. The hepatic encephalopathy appears to be getting worse.

A delirium work up is done. Nothing new is found.

What will you do? Why?

Answer 37

◆ Trial of rifaximin

◆ Several trials have demonstrated its efficacy in relieving symptoms of encephalopathy, reducing blood ammonia levels and improving electroencephalographic abnormalities

Question 38

List FOUR complications of ERCP/PTC

Answer 38

◆ Bleed
◆ Biliary leak
◆ Acute pancreatitis
◆ Bacterial cholangitis

Question 39

What does PTC stand for and what intervention is usually done?

Answer 39

◆ Percutaneous Transhepatic Cholangiogram
- Percutaneous Biliary Drainage (PBD)

Question 40

List the SIX complications (6) of a peritoneovenous shunt (shunt placed into ascites and then tunnelled under the skin to the systemic circulation, usually the internal jugular or femoral veins)*

Answer 40

◆ Most common:
- lumen occlusion as a result of thrombosis
- DIC

◆ Less common:
- fluid overload with pulmonary edema
- thromboembolism
- vena caval thrombosis
- hepatic encephalopathy
- peritonitis
- tumor seeding to SC of ant abdo wall

Question 41

Name FOUR pharm tx for cholestasis induced pruritis

Answer 41

◆ Removal of puritogens
- cholestyramine, colestipol, colesevelam
◆ Enzyme induction
- rifampin
◆ Opioid antagonist
- naloxone, naltrexone
◆ Serotoninergic systems
- sertraline, paroxetine