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Gastroenterology > Liver Disease > Flashcards

Liver Disease Flashcards

1
Q

What is the significance of the AST:ALT ratio?

A
  • AST ALT, but not in ratio >2:1
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2
Q

Features of acute liver failure:

A
  1. acute hepatocellular injury (usually >10xULN) - less than 26 weeks.
  2. hepatic encephalopathy
  3. prolongation of PT, or INR ≥1.5

In previously normal individual - no preexisting cirrhosis / CLD.

Note: may have previously asymptomatic, undiagnosed, underlying liver disease (eg. HBV, AI, Wilson’s).

Commences with fatigue / malaise, anorexia, nausea, RUQ pain, jaundice. Then develop encephalopathy (can rapidly progress)

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3
Q

Ischaemic hepatitis / shock liver: approximate magnitude of aminotransferase elevation?

A

AST & ALT >50xULN

LDH also often elevated.

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4
Q

NAFLD: approximate magnitude of aminotransferase elevation?

A

AST & ALT usually <4xULN

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5
Q

Investigation of aminotransferase elevations:

A

Toxicology screen, incl. paracetamol level (especially if marked elevation).

Viral hepatitis serologies.

Pregnancy test. Urinalysis if pregnant.

Autoimmune markers: ANA, anti-SM Abs, anti-LKM (liver kidney mitochondrial) Abs Type 1, IgG levels. Serum EPP.

USS with doppler (cirrhosis, fatty liver, rule out vascular occlusion).

+/- Cerulosplasmin, urinary copper excretion (if features of Wilson’s).

+/- Hepatitis D if HBV positive
HEV

+/- Alpha1 AT levels and phenotyping

+/- TFTs & T3; coeliac antibodies (mild - mod derangement)

+/- evaluation for adrenal insufficiency if clincally suspicious

+/- Serum CK / CK aldolase if suspect muscle disorder (AST).

If AST and ALT Expectant observation acceptable after workup.

Otherwise –> LIVER BIOPSY
(useful in marked elevation; more as a reassurance in mild-mod elevations)

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6
Q

ALP elevations - aetiology:

A

Usually at least 4xULN in cholestasis
o Level of rise does not distinguish intrahepatic from extrahepatic causes of cholestasis → would need imaging to distinguish (start with TA USS)
o GGT may also be elevated but non-specific

Lesser degrees are nonspecific and may be seen in: other types of liver disease, such as viral hepatitis, infiltrative disease of the liver, congestive hepatopathy.

Bone and placenta are other sources of ALP
o If bilirubin or other LFTs deranged, usually liver presumed as origin
o If GGT normal then evaluate for bone disease

ALP raised in setting of high bone turnover: healing fracture, osteomalacia, hyperparathyroidism, hyperthyroidism, Paget disease of bone, osteogenic sarcoma, bone mets.
Ix: serum calcium, PTH, vitamin D, bonescan

If liver origin, isolated (no other LFT derangement) and persistant, consider:
o Chronic cholestatic disorders: PBC, PSC, partial bile duct obstruction
o Drugs, eg. androgenic steroids, phenytoin
o Infiltrative diseases: sarcoidosis, amyloidosis, liver mets

Acute or chronic elevation of the alkaline phosphatase in conjunction with other LFT abnormalities may be due to extrahepatic causes (eg, common bile duct stones, primary sclerosing cholangitis, malignant biliary obstruction) or intrahepatic causes (eg, PBC, primary sclerosing cholangitis, infiltrative disease).

Investigation of cholestasis begins with USS → ?intrahepatic or extrahepatic

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7
Q

Cholestasis - Aetiology: Extrahepatic vs Intrahepatic:

A

EXTRAHEPATIC CHOLESTASIS:

  • DDx: choledocholithiasis, malignant obstruction (pancreatic, GB, ampulla, bile duct cancer), PSC, chronic pancreatitis with structuring of the distal bile duct (rare), AIDS cholangiopathy
  • ERCP / MRCP / CT / Liver biopsy

INTRAHEPATIC CHOLESTASIS:
- Consider drug cause – eliminate and observe (though may take months)
- Test AMA (antimitchondrial antibodies)
• Positive → liver biopsy ?PBC
• Negative → further testing warranted
- AMA negative:
• MRCP: exclude PSC
• Hepatitis serology (A,B, C, E)
• EBV and CMV serology
• Pregnancy test in women of child bearing age (cholestasis of pregnancy)
- Other causes: benign post-operative cholestasis, TPN, infiltrative diseases (eg. sarcoidosis or malignancy), vanishing bile duct syndrome, adult bile ductopaenia.
- If these tests are negative and ALP >50% above ULN for >6/12 → liver biopsy to look for some of these other causes
- However, if ALP <50% above ULN, other LFTs normal and patient is asymptomatic then observation alone is acceptable (further testing unlikely to alter management)

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8
Q

Acute liver failure: 3 syndromes based on “jaundice-to-encephalopathy time”:

A
  1. Hyperacute (Fulminant) hepatic failure: 1 week
  2. Acute liver failure: 8-28 days
  3. Subacute liver failure 29 days - 12/26 weeks (depending on definition)

Hyperacute / acute present with cerebral oedema.

Subacute present more like decompensated cirrhosis (eg. renal failure, complications of portal HTN).

Prognosis best in hyperacute (probably because most are due to paracetamol - NAC).

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9
Q

Aetiology of acute liver failure:

A

Series 1998-2001 US:

  1. Paracetamol toxicity (39%)
  2. Indeterminate (17%)
  3. Idiosyncratic drug reactions (13%)
  4. Viral hepatitis (A or B) (12%)

Other:
- Viral: A, B +/- D
HSV (pregnancy 3rd tri, or immunocompromised), HEV (pregnancy 3rd tri), CMV, EBV, varicella
- Drugs and toxins, incl. herbal
- Vascular: Budd-Chiari, VOD, RHF, Ischaemia hepatitis
- Metabolic: acute fatty liver of pregnancy, Wilson’s disease, Reye’s syndrome
- AIH
- malignant infiltration
- sepsis

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10
Q

Paracetamol toxicity - patterns of ingestion:

A
  1. single acute ingestion
  2. repeated ingestion supratherapeutic dose
  3. therapeutic misadventure: overdose at therapeutic dose; usually if on inducers of P450 system or fasting alcohol with pre-existing liver disease (glutathione depleted).

Paracetamol hepatoxicity = raised ALT +/- raised INR

Paracetamol-induced acute liver failure = raised ALT and INR + hepatic encepaholpathy

Leading cause of ALF WITH AN AVAILABLE ANTIDOTE.
Even if evidence lacking perform para level.
However, low or undetectable levels do not rule it out –> if suspect, start NAC.

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11
Q

Transminases in thousands… think of which 4 aetiologies?

A

Paracetamol
Inchaemic hepatopathy
AI hepatits
Acute viral hepatitis

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12
Q

NAC in paracetamol-related liver injury - general protocol:

A 
Best early (within 8hrs of OD) - ie. BEFORE ALT elevation.
Late administration in ALF still decreases mortality and improves hepatic cerebral function.
  1. no ALT rise: standard protocol
  2. Hepatotoxicity: std protocol + 20hr infusion.
    Continue until paracetamol level undetectable (repeat daily) + decreasing ALT (peaks in 1-2 days) + INR <2.0
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13
Q

King’s College Criteria

A

Indication for Transplantation:
- INR elevated and rising:
INR ≥3.6 at 36 hours post-OD –> early transfer to transplant centre for evaluation

Psychiatric evaluation (before encephalopathy) –> ?suitable candidate for transplantation.

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14
Q

Drug-induced hepatotoxicity - usual timeframe

A

Paracetamol acute: dose-related hepatotoxicity.

Most others are idiosyncratic reactions.

Usually occur within 1st 6 months of drug initiation.

eg. Antibiotics, NSAIDs, AEDs, Herbal, Ecstasy.

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15
Q

Wilson’s disease is an uncommon cause of acute liver failure.
Why and when is it important to test for it?

A

Early recognition is important as the fulminant presentation of Wilson’s disease is considered to be uniformly fatal without liver transplantation.

Typical presentation:

  • young patients
  • abrupt onset of haemolytic anaemia (elevated unconjugated bilirubin, not just conjugated).
  • K-F rings only 50% patients
  • Low ceruloplasmin 85%
  • High serum and urinary copper levels.

Clues to Dx:

  • low serum ALP or uric acid levels
  • high bili:ALP (>2)
  • renal impairment common (released copper damages renal tubules)

Treatment:
- Acutely lower serum copper: Albumin dialysis / CVVHD / plasmapharesis
(avoid penicillamine due to risk of idiosyncratic reactions)
- Liver transplantation (universally fatal without this).

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16
Q

Wilson disease (hepatolenticular degeneration):

A
  • Due to a genetic abnormality that leads to impairment of cellular copper transport
  • AR inheritance
  • worldwide prevalence 1/30,000 live births.
  • Impaired biliary copper excretion leads to accumulation of copper in several organs, most notably the LIVER, BRAIN and CORNEA.
  • Over time, the liver is progressively damaged and eventually becomes cirrhotic.
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17
Q

Clinical presentation of Wilson disease:

A

Clinical presentation of Wilson disease:

Usually becomes clinically apparent 5-35yo (but can be Dx younger or much older).

  1. Chronic liver disease.
    A small percent of patients develop acute liver failure, most often in the setting of advanced fibrosis of the liver.
  2. Neurologic: varied presentations; can be acute or gradual onset. Progressive. May commence as: dysarthric, dystonic, tremulous, pseudosclerotic (tremor with or without dysarthria), or parkinsonian. Dysarthria most common symptom. Most with neuro symptoms have K-F rings.
  3. Psychiatric
    eg. behaviour / personality change, loss of inhibition, mood disorder, cognitive impairment (eg. decline in school performance).
  4. Haemolytic anaemia - occurs in ALF associated with Wilson’s disease
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18
Q

Investigations for Wilson Disease:

A
  • LFTs (AST and ALT derangement; low ALP)
  • FBC +/- DCT (haemolytic anaemia)
  • Serum ceruloplasmin
  • Serum copper level
  • Urinary copper excretion
  • Ocular slit lamp examination
  • MRI (if neurological symptoms)
  • Tests to rule out other causes of presentation
  • Liver biopsy –> hepatic copper concentration
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19
Q

Treatment of Wilson Disease:

A

Requires life-long treatment. Two phases: (1) removing or detoxifying the tissue copper that has accumulated and (2) preventing reaccumulation.

(1) Copper removal with potent chelators:
- D-penicillamine (but significant ASEs - approx. 30% do not tolerate long-term)
- Trientine
- These are thought to be safe in pregnancy, but need to dose-reduce.

(2) Prevention of reaccumulation:
- Chelators (reduce dose by 33% from initial Tx).
- Zinc salts: prevent copper absorption but may also increase the levels of the detoxifying protein metallothionein in liver itself.
- Newer agents awaited.
- Low copper diet important:
Avoid liver, kidney, shellfish, nuts, dried fruits or beans, peas, unprocessed wheat, chocolate, cocoa, and mushrooms.

(3) In acute liver failure due to Wilsons disease:
- Acutely lower serum copper: Albumin dialysis / CVVHD / plasmapharesis
(avoid penicillamine due to risk of idiosyncratic reactions)
- Liver transplantation (universally fatal without this).

20
Q

Acute ischaemic liver injury (“shock liver”) - diagnosis:

A

Occurs after cardiac arrest or period of signficant hypotension, or in setting of severe CHF.
(Documented hypotension not always found).

AST and ALT markedly elevated (eg. >50xULN), but respond rapidly to CVS stabilisation.

Treatment: just of underlying CV condition.

21
Q

What is Budd-Chiari Syndrome?

A

Liver injury due to hepatic venous outflow obstruction (ie. obstruction can occur in small or large hepatic veins, or IVC).
[Liver failure due to constrictive pericarditis and RHF not B-C though].

Usually associated with underlying myeloproliferative disorder (may be first / only manifestation).

87% have a RF for thrombosis, eg. JAK2 mutation, Factor V Leiden mutation, PT gene mutation, APL antibodies.

Can present acutely (ALF - abdo pain, ascites, striking hepatomegaly) / subacutely / chronically / asymptomatically.

22
Q

Encephalopathy stages:

A

Stage 1:
Euphoria, mental slowing, alternation of sleep / wake cycle, mild confusion / slurred speech.

Stage 2:
As above, + drowsiness, inappropriate behaviour, incontinence.

Stage 3:
Sleeps most of the time but rousable, incoherent speech, marked confusion

Stage 4:
Not rousable, may or may not respond to painful stimuli

Tremor (asterixis):
1: Slight
2&3: Present
4: N/A

EEG:
1: Usually normal
2: Generalised slowing
3&4: Always abnormal

23
Q

Cerebral oedema is the most severe complication of ALF.

How often does it occur?

A

Rates of cerebral oedema in ALF related to the severity of encephalopathy:

25-35% Grade III HE
65-75% Grade IV HE

Risk of uncal herniation and death.
Also risk of hypoxic brain injury –> long term neurological sequelae in survivors.

Signs:

  • Cushings Reflex (systemic HTN and bradycardia)
  • Decerebrate rigidity
  • Disconjugate eye movements
  • Loss of pupillary reflexes
  • Seizure activity
24
Q

What are the Kings College Criteria for Liver Transplantation for ALF related to PARACETAMOL?

A 
pH 100secs (INR >6.5)
3. Serum Cr >300 umol/L

Predict who will benefit from transplantation.

These criteria are highly predictive of poor outcome when fulfilled (10-15% survival).
HOWEVER, not able to predict those at low risk of dying.
Ie. PPV for poor outcome is good, 70-100%; NPV is low.
This means that lack of criteria fulfilment does not guarantee survival.

25
Q

What are the Kings College Criteria for Liver Transplantation for NON-PARACETAMOL-related ALF?

A

PT >100secs (INR >6.5) irrespective of HE grade

Or any 3 of:

  1. Age 40
  2. Aetiology:
    - non-A, non-B hepatitis
    - halothane (now uncommon)
    - idiosyncratic drug reaction
    - Wilson’s disease
  3. Jaundice to HE time >7days (ie. acute or subacute)
  4. PT >50secs (INR >3.5)
  5. Serum bili >300 umol/L
26
Q

CLD: MELD score cut-off for considering liver transplantation?

A

MELD score ≥15 –> consider transplantation in chronic liver disease.

Note: no MELD cut-off used in ALF (use Kings College Criteria instead), though correlates with prognosis.

27
Q

Treatable underlying causes of acute liver failure?

A

Paracetamol –> NAC

HSV –> acyclovir

AFLP (acute fatty liver of pregnancy) –> rapid delivery of infant

Amanita mushrooms –> penicllin and silibin (milk thistle).

Note: no specific treatment for ALF, need to treat underlying cause, supportive care, anticipate complications, consider transplant.

28
Q

Liver transplant categories

A

Cat 1:

  • ALF when I&V in ICU
  • priority over all transplants in Aust & NZ

Cat 2: ALF not I&V

Cat 3:
- CLD with MELD >15
- MELD exceptions (eg. polycystic disease, PSC with recurrent cholangitis, severe prutitis in PBC / PSC, HPS and portopulmonary syndrome).
HCC = MELD 22.

29
Q

Parameters assessed in Childs-Pugh Score for Cirrhosis:

A

Must have evidence of Cirrhosis.

Parameters:

  • Ascites
  • Albumin
  • Bilirubin
  • Encephalopathy (grade)
  • PT / INR
Scores (5-15):
Grade A (well compensated) = 5-6
Grade B (significant functional compromise) = 7-9
Grade C (decompensated liver disease) = 10-15.
30
Q

Hepatitis - proportion of new cases contracted by injection drug use?

A

Approx. 90% in Australia

Note: risk of sexual transmission is low.

31
Q

What is the commonest cause of end stage liver failure requiring transplant?

A

HCV

32
Q

What is thought to be the main driver of the worldiwde HCC / liver cancer epidemic?

A

HCV (+/- alcohol use)

33
Q

Why is HCV more curable than HBV?

What types of virus are HBV and HCV?

A

Because it exists in the cytoplasm, rather than viral RNA being incorporated into host DNA.

HBV: ds DNA virus
HCV: single stranded RNA virus

34
Q

There are 6 major HCV genotypes (and there may be another three - ie. 7,8 , 9 - in SE Asia).
Which are most common in Australia?
What is the significance of this?

A

Genotypes 1 and 3 are common in Australia.

Genotype is the key determinant in effectiveness of treatment.

Genotype 2 & 3 more susceptible than 1.
Subtype 1b more susceptible than 1a.

Each person only infected with one dominant genotype, but multiple quasispecies (develop due to genetic mutations).

35
Q

HCV antibodies are not neutralising.
What does this mean?
What is the implication?

A

The antibodies do not neutralise the antigen to which they form.
Therefore they do not give any immunity.
This is the reason an immunisation to HCV has not yet been developed.

36
Q

PCR for HCV RNA - is it sensitive?

A

Yes, very.

A negative test months after infection implies no viral replication (ie. that infection has been cleared).

37
Q

HCV transmission in pregnancy:

A

Low risk of vertical transmission (approx. 4% if mother PCR positive), but increased risk with HIV co-infection.

Not an indication for termination.
No evidence not to breast feed.
Note: babies will test positive at birth (passively acquired antibodies).

38
Q

Needle-stick infection risks with BBVs (hollow needle):

A

HIV approx. 0.3-0.4%
HCV approx. 3-4%
HBV approx. 30-40%

39
Q

Definition of sustained virological response (SVR) in HCV treatment?

Definition of rapid virological response (RVR) and implication?

A

SVR = patient remains PCR negative 6 months after cessation of treatment.

RVR = no detectable virus after 4 weeks of therapy.
Implies high probability of SVR.

Absence of RVR - treatment unlikely to work (used to exclude from ineffective treatment.

40
Q

Benefits of successful HCV treatment:

A
  • reversal of liver fibrosis / early cirrhosis
  • decrease risk liver cancer
  • decreased risk cirrhosis & decompensation
  • decreased infectivity
  • improved QoL, productivity; less absenteeism
41
Q

Treatment of HCV (by genotype):

A

Genotype 1 & 4:
48 weeks of pegylated interferon + ribavirin + a direct-acting antiviral (ie. protease inhibitors).

[P.I.s available in Aust for HCV = Teleprevir and Boceprevir. They increase rates of SVR from 40-50% to approx 70% in Genotype 1].

Genotype 2 & 3:
24 weeks PEG-IF and Ribavirin
(48 weeks if cirrhotic)

42
Q

Ribavirin:
Mechanism?
Major ASEs / precautions?

A

Nucleoside analogue.
Mechanism in HCV incompletely understood.
Doesn’t work as monotherapy.

Dose-dependent haemolysis –> anaemia.
Potent teratogen –> men and women require double contraception.

43
Q

Pegylated interferon:

A

Alpha 2a or alpha 2b interferon (cytokines usually produced by lymphocytes). However, short t1/2.

Polyethylene glycol molecule is attached to standard interferon molecule.

Pegylation slows absorption and metabolism, reduces immunogenicity (but doens’t affect IFN action).
Administered weekly.

44
Q 
Protease inhibitors (teleprevir and boceprevir). 
Major ASEs / precautions:
A

Rash and anaemia.
Multiple drug-drug interactions.
Require tight dosing schedule.
Rapid emergence of viral resistance unless used with PEG + RBV.

[Await second generation P.I.s which should be available soon and less ASEs]

45
Q

What is sofosbuvir?

A

Sofosbuvir = Nucleoside analogue.

Shown to be effective in HCV treatment.
New agent, not yet in use.
Decreased ASEs (?may be able to avoid IFN in genotype 2&3); increased rates of SVR.

46
Q

What is the influence of age of infection on HBV infection chronicity?

A

Age ≤2yo –> 40% chance chronic HBV.

Age >2yo –> greater chance of acute hepatitis; approx. 5% chance chronic HBV.

47
Q

Patients with HBV who have had resistance to lamivudine. Should they be given entecavir or tenofovir?

A

Tenofovir.

Entecavir has cross-resistance with Lamivudine and is best used in lamivudine-naive patients.

Gastroenterology (7 decks)

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