tbl 5 clinical: Liver failure

Question 1

Acute liver failure (ALF) – rare but devastating entity, which develops after a severe liver insult
- Severe acute liver dysfunction – jaundice, coagulopathy (____________) and encephalopathy in a patient without pre-existing liver disease

• Characterised by rapid development of coagulopathy and encephalopathy
• ALF is potentially reversible through liver regeneration
• Can be subdivided into hyperacute (<1 week), acute (1 to 4 weeks) and subacute (>4 weeks) – dependent on the length of time from hepatic injury to the development of encephalopathy
• This classification may give clue about aetiology as well as prognosis
  o e.g. hyperacute ALF may be secondary to paracetamol overdose or acute hepatitis _______, whereas subacute ALF may be secondary to nonparacetamol drug induced liver injury or _______________
  § Generally, subacute ALF has worse prognosis
• Patients with acute liver failure may be asymptomatic, or present with non-specific symptoms, such as fatigue, malaise, lethargy, right upper quadrant discomfort, anorexia, nausea and vomiting
  o They may be icteric, complain of jaundice and/or pruritus
  o Subacute ALF – may complain of ____________ due to ascites
  o Mental status may correlate with severity of encephalopathy – can be subtle mental change in milder cases to comatose in more severe cases

Answer 1

INR ≥ 1.5;

A or E;

autoimmune hepatitis;

abdominal distension;

Question 2

4 grades of hepatic encephalopathy

Grade Behaviour

• 1 Changes in behaviour, mild confusion, slurred speech, disordered sleep
• 2 __________, moderate confusion
• 3 Marked confusion, incoherent speech, sleeping but ___________
• 4 Coma

Causes of ALF

• Infection: HAV, HBV, HDV, HEV, EBV, CMV, HSV, varicella
• Drugs: Paracetamol, anti-TB, anti-retroviral, ecstasy, halothane, NSAIDs, anti-convulsants
• Metabolic: Wilson’s, Reye’s
• Vascular: Budd chiari, VOD (veno-occlusive disease)
• Others: Fatty liver of pregnancy, lymphoma, amanita phalloides, trauma

Epidemiology – in the west, Paracetamol overdose is the most common cause, whereas in the east, including Singapore, ________ is the major culprit.

Answer 2

Lethargy;

wakes with stimulation;

viral hepatitis

Question 3

Clinical features of ALF

• Acute liver failure causes significant morbidities which can be fatal
• Multiple organ failure is universal in ALF
• Brain: Hepatic encephalopathy, cerebral oedema and ___________
• Lung: Acute lung injury and ______________
• Heart: High output state and frequent subclinical myocardial injury
• Liver: Loss of metabolic function; Hypoglycaemia due to decreased __________; Lactic acidosis due to decreased _____________; Hyperammonaemia due to decreased ammonia clearance; __________ due to reduced synthetic capacity of coagulation proteins
• Pancreas: Pancreatitis, particularly in _______________
• Adrenal gland: Inadequate __________ production contributing to hypertension
• Kidney: Frequent dysfunction or failure
• Bone marrow: Frequent suppression, particularly in viral and seronegative disease
• Portal hypertension: May be prominent in subacute disease and confused with chronic liver disease
• Circulating leukocytes: Impaired function, with ___________ contributing to high risk of sepsis
• Systemic inflammatory response: High energy expenditure or rate of catabolism
• Specific clinical features of ALF include –
  o Hepatic encephalopathy
  o Intracranial hypertension – major cause of early mortality of ALF as it causes cerebral oedema of brainstem herniation
  o Coagulopathy
  o Metabolic – decreased levels of glucose, potassium, sodium and metabolic acidosis
  o Infection – many transplant centers advocate __________________

Answer 3

intracranial hypertension;

acute respiratory distress syndrome;

gluconeogenesis; lactate clearance; Coagulopathy;

acetaminophen-related disease;

glucocorticoid;

immunoparesis

empirical antibiotics and antifungal therapy

Question 4

Management of ALF
- Goals of treatment in ALF are to identify and to treat the underlying aetiology and to provide supportive care to prevent complications

• Aetiology-specific treatment such as ______________ for paracetamol overdose, antiviral therapy for hepatitis B, immunosuppression with steroid for autoimmune hepatitis, and ___________ for Wilson’s disease, must be started promptly
• Supportive management – optimisation of nutrition including early use of _____________, empirical antibiotics and antifungal to prevent infection, careful fluid management and consideration of early renal replacement therapy
• ICU management including intubation is crucial for those with ALF and grade 3 hepatic encephalopathy
  o Early discussion and transfer to liver transplant center if indicated

Answer 4

N-acetylcysteine; D-penicillamine;

enteral nutrition

Question 5

Liver transplant for ALF
- King’s College Criteria – used to determine poor prognosis in ALF, hence the need for liver transplant
o It has criteria for paracetamol-induced ALF and non-paracetamol induced ALF
o Without liver transplantation, patients who fulfill the King’s College criteria are unlikely to survive

Paracetamol induced acute liver failure

• arterial pH < ____
• any 3 of the following: PT >100s, INR > ___. creatinine > _____ umol/litre and grade 3-4 encephalopathy

Non paracetomol induced ALF

• prothrombin tme > 100 seconds or
• any 3 of this: unfavourable aetiology (seronegative hepatitis or idiosyncratic drug reaction), prothrombin time > 50 seconds, serum bilrubin > 300umol/litre, jaundice to encephalopathy time > 7days, age > 40 or < 10 years old

Answer 5

7.3, 6.5, 300

Question 6

Chronic liver failure (CLF) – cirrhosis
- Chronic liver failure or end stage liver disease is the late stage of liver cirrhosis
o __________ is a dynamic process, repetitive liver injury with progressive liver fibrosis will culminate to the point of no return when cirrhosis is formed

Cirrhosis – a complication of chronic liver disease
- It is irreversible, characterised by destruction of hepatocytes and formation of networks of fibrosis with regenerating nodules
o Although it is a histological diagnosis, ___________ is rarely required to make the diagnosis – complications of liver biopsy include bleeding, infection, injury to surrounding organs, death
- Biochemically, may manifest as having depressed synthetic function i.e. low albumin and prolonged INR
o For more advanced liver cirrhosis, bilirubin will also be elevated
o With the presence of portal hypertension, there is __________________ due to splenic sequestration

Imaging – ultrasound may show nodular shrunken liver with coarsened echotexture
o However, ultrasound may show a normal looking liver even in the presence of cirrhosis
o Splenomegaly may be present due to portal hypertension.

• Measurement of liver stiffness – _______________
  o Measure the velocity of a vibration wave, also called shear wave generated on the skin
  o Shear wave velocity is determined by measuring the time the vibration waves take to travel to a particular depth inside the liver
  o Fibrous tissue is harder than normal liver – degree of hepatic fibrosis can be inferred from the liver hardness
• Important to note that patients with established liver cirrhosis may present with normal liver function tests as well as relatively normal ultrasound scan

Answer 6

Fibrogenesis;

liver biopsy;

thrombocytopenia;

Fibroscan or MR elastography

Question 7

Aetiology of cirrhosis – can be broadly categorised into viral, autoimmune, metabolic, and miscellaneous.

• In the West, alcoholic liver disease and chronic hepatitis C are the major causes, and nonalcoholic fatty liver disease is rising rapidly
• Locally in Singapore, just like many Asia Pacific countries – ______________ is the most common cause, followed by alcohol, ___________ and chronic hepatitis C

Symptoms of cirrhosis
- Clinical manifestation of cirrhosis may be asymptomatic, or may include nonspecific symptoms such as anorexia, nausea, weight loss, fatigue
- Patients with compensated cirrhosis are usually asymptomatic, or may have nonspecific symptoms such as anorexia, nausea, weight loss, fatigue
- For patients with decompensation, their symptoms may be secondary to the decompensation such as jaundice, pruritus, abdominal distension from ascites, gastrointestinal bleeding, or confusion due to encephalopathy
o Decompensated cirrhosis is defined by the development of _______________________

Answer 7

chronic hepatitis B; cryptogenic;

jaundice, ascites, variceal haemorrhage, or hepatic encephalopathy;

Question 8

Clinical features of liver failure due to cirrhosis – presence of any of these signs prompt the
physician to suspect there is already underlying liver cirrhosis
- Encephalopathy, liver flaps, jaundice, porto-pulmonary hypertension and hepatopulmonary syndrome
o Hepatopulmonary syndrome – shortness of breath and ____________ (low oxygen levels in the blood of the arteries) caused by vasodilation (broadening of the blood vessels) in the lungs of patients with liver disease
- Muscle wasting, weakness and ascites
- Leukonychia, palmar erythema and dupuytrens contracture
o ____________ – white, horizontal bands across the nails are the result of low albumin levels in the blood
o ____________ – one or more fingers become permanently bent in a flexed position
- Testicular atrophy or amenorrhoea
- Peripheral oedema and scratch marks

Staging of cirrhosis – Child-Pugh score
- Stages liver cirrhosis according to 2 clinical parameters (ascites, encephalopathy) and 3 laboratory parameters (bilirubin, albumin and INR)
- Total score ranges from 5 to 15
o Class A – considered well compensated cirrhosis
o Class B – considered significant functional compromise
o Class C – considered decompensated cirrhosis
- Child Pugh classification correlates with patients’ survival

Answer 8

hypoxemia;

Leukonychia;

Dupuytrens contracture;

Question 9

Stages of cirrhosis
- Compensated cirrhosis – any sign of decompensation confers poor prognosis with reduced median survival
- Without decompensation, 1- year mortality is around 1%, and 5-year survival approximates 80%
- Once decompensation occurs with ascites, 1-year mortality increases rapidly to 20% and 2-year survival is down to 50%
o Once decompensation occur, median survival reduces 12 to 48 months
o With each episode of variceal bleeding there is a 20% risk of mortality
- stage 1: no varices, no ascites
- stage 2: ___________
- stage 3: ____________
- stage 4 _________________

Answer 9

varices no ascites;

ascites +/- varices;

bleeding +/- ascites

Question 10

Complications of cirrhosis
- 3 common complications of cirrhosis are hepatic encephalopathy, ascites and varices

1. Varices
   - ______________ leads to formation of collateral – portal blood flows through these channels in an attempt to circumvent the resistance of the liver
   o e.g. oesophageal varices, caput medusa, ___________ and rectal varices

• 30% of compensated cirrhosis and 60% of decompensated cirrhosis have oesophageal varices at the time of diagnosis
• _______________ is recommended.
• Oesophageal varices – extremely dilated sub-mucosal veins in the lower third of the oesophagus
• Patients at increased risk for variceal bleeding i.e. those with Child’s class B or C cirrhosis, larger varices or with red signs on the varices should receive primary prophylaxis
  o Primary prophylaxis can be in the form of non-selective beta blocker such as propranolol, or ___________________
  o For patients who have recovered from an episode of bleeding, they should receive both beta blocker and EVL as secondary prophylaxis to prevent recurrent bleeding
• In the acute setting of variceal bleeding pharmacotherapy causing splanchnic vasoconstriction and decreased portal inflow such as _____________ should be used in conjunction with EVL
• In the event of failure to achieve haemostasis – __________________ should be inserted
• Salvage therapy – transjugular intrahepatic portosystemic shunt (TIPS) to shunt the portal flow to the systemic circulation hence reducing portal pressure

Answer 10

Portal hypertension;

splenorenal shunt;

Screening gastroscopy;

endoscopic variceal ligation (EVL);

terlipressin or somatostatin;

balloon tamponade with Sengstaken-Blackmore tube

Question 11

2. Ascites – pathological accumulation of fluid within
   peritoneal cavity, 80% are due to liver cirrhosis
   - Ascites is the most common complication of cirrhosis
   - ______________ should be performed and ascitic albumin should be checked – difference or gradient between serum albumin and ascitic albumin should be calculated
   o Serum-ascites albumin gradient (SAAG) ≥ 11g/L indicates portal hypertension as aetiology

• Treatment of ascites generally consists of salt restriction, spironolactone, and frusemide
  o Tense ascites – can be treated with _____________ with albumin cover
  o Refractory ascites (not responsive to diuretics) – can be treated with large volume paracentesis or TIPS

Answer 11

Diagnostic tap;

large volume paracentesis

Question 12

3. Hepatic encephalopathy
   - Can be classified into covert and overt apart from the grade I to IV classifications
   o Covert – subclinical, may only be diagnosed with psychometric or neurophysiologic tests
   o Overt – once there is asterixis or disorientation
   - Treatment of HE – to identify and treat accordingly if there is any precipitating factor such as GI bleeding, infection including spontaneous bacterial peritonitis (SBP), electrolyte disturbance, dehydration, acute kidney injury, constipation and iatrogenic such as sedative medications
   - Pharmacotherapy for HE is _________
   - _________, a non-absorbable antibiotic, can be used as a second line for refractory HE

Answer 12

lactulose;

Rifaximin

Question 13

Liver transplantation
- Patients with end stage liver disease without contraindication for liver transplant should be referred to a transplant centre for further assessment when their MELD score is rising towards 15
- MELD score – Model for end-stage liver disease core, a prospectively developed and validated scoring system
o Formula based on INR, bilirubin and creatinine to predict 3- month mortality
o Worldwide, it is now used to prioritise allocation of donor organ for patients in need of liver transplantation
o The range of MELD is from 6 to 40 – higher score signifies worse prognosis
o There is survival benefit with liver transplantation for patients with MELD score of ≥15
MELD = _________________________
o Because hyponatraemia is an independent predictor of mortality, it is now incorporated into the MELD sore as the MELD-Na score, for organ allocation purpose
- MELD score is superior to Child-Pugh’s score and preferred in most transplant centres worldwide
o MELD includes creatinine (a measure of kidney function) – most patients with end stage liver disease die from multiple organ failure (including and especially kidney)

Answer 13

3.78×ln [serum bilirubin (mg/dL)] + 11.2×ln [INR] + 9.57×ln [serum creatinine (mg/dL)] + 6.43