Acute Hepatitis Including Acute Liver Failure

Acute Hepatitis
Including Acute Liver Failure
Stefan Hübscher, School of Cancer Sciences, University of Birmingham.
David Mutimer, Liver Unit, Queen Elizabeth Hospital, Birmingham

Acute liver failure
Acute Liver Injury

Acute Liver Failure (ALF)
FHF and LOHF
• FHF : fulminant hepatic failure
“The development of encephalopathy within 8
weeks of the onset of symptoms, without
previous liver disease.”
• LOHF : late onset hepatic failure
“Encephalopathy appears after 8 weeks, but
within 6 months of symptom onset.”
‣ subacute hepatic necrosis
‣ subacute hepatic failure

Acute Liver Failure (ALF)
FHF and LOHF
• FHF
‣ paracetamol poisoning
‣ coagulopathy + +
‣ cerebral oedema + +
‣ hypoglycaemia
‣ may present before jaundice
‣ potential for recovery with conservative care
• LOHF
‣ seronegative hepatitis (non-A, non-B)
‣ coagulopathy +
‣ ascites +
‣ jaundice ++
‣ renal failure
‣ conservative care fails, transplant indicated

Acute Liver Failure Admissions
Birmingham Liver Unit 1987-2007
1000
800
600
400
200
0
Seronegative
AFLP/HELLP
Other drug/toxin
Miscellaneous
POD
Viral
AVOD
Wilsons
Budd Chiari

Acute Liver Injury
Patient Management
• Aetiology
• Severity
• Prognosis

Acute Liver Injury
Establishing the Aetiology
History
• drug exposure
‣ prescription
‣ non-prescription
‣ herbal
• psychiatric and psychosocial issues
• exposure to hepatitis viruses
‣ travel (hepatitis A or E)
‣ sex (hepatitis B)
‣ blood exposure (hepatitis C or B)
Examination
• absence of signs of chronic liver disease
• liver size

Acute Liver Injury
Establishing the Aetiology
Blood tests
• routine biochemistry
‣hyperacute (high transaminases, lower bilirubin)
• paracetamol, ischaemia, hepatitis B
‣subacute (lower transaminases, higher bilirubin)
• seronegative hepatitis
‣Wilson’s disease (low alkaline phosphatase)
• paracetamol detection
• viral serology
‣IgM antibodies to HAV, HBV, HEV
• liver immunology
‣autoantibodies, immunoglobulins

Acute Liver Injury
Establishing the Aetiology
Imaging
• ultrasound
‣ liver size and texture
‣ spleen size
‣ ascites
‣ oedematous gall bladder
‣ infiltration
• ? CT scan
Biopsy
• how will the histology influence management?
• problems
• bleeding
• cerebral oedema
• misinterpretation of histology (by the pathologist)
• clinician over-reliance on histological diagnosis
• delays definitive treatment

Acute Liver Injury
Establishing the Severity & Prognosis
• Aetiology
‣ paracetamol poisoning has unique prognostic criteria
‣ seronegative hepatitis has poor prognosis
• Duration of illness
• Clinical features
‣ shrinking liver
‣ ascites
• Biochemistry limited value
• Coagulation important

Case 1

Case 1
• 52 year old Caucasian male
• GP referral to surgeons with “obstructive jaundice”
• US and MRCP (stones in gall bladder, spleen 13 cm)
• liver biochemistry
• refer to physicians (seen 2 weeks later in clinic)
• ALT 1263, bilirubin 250, INR 1.1 (and stable for 2 weeks)
• viral serology negative
• immunology
• antinuclear antibody and anti smooth muscle antibody positive
• slightly elevated immunoglobulins
• diagnosis: aetiology and severity?
• acute autoimmune hepatitis (can be underlying chronic damage)
• no evidence of liver failure (not incipient)
• liver biopsy

Liver Biopsy in Acute Hepatitis
Histological Approach
1. Is this acute or chronic damage?
2. How severe is the damage?
3. What is the cause?

Case 1

Case 1

Case 1

Case 1 - ductular reaction
CK7 immunostaining

Case 1

Case 1

Case 1

Case 1 (PAS-diastase)

Case 1 (PAS-diastase)

Acute Hepatitis
Hepatocyte Proliferation (Ki 67 immunostaining)

Case 1 (Perl’s)

Case 1 (HVG)

Case 1
Histological Findings
• Portal inflammation
– mainly mononuclear with plasma cells
• Bile ductular reaction
• Spotty lobular inflammation, associated with
– Ballooning
– Acidophil body formation
– Lobular disarray
– Small foci of confluent necrosis
– Bilirubinostasis (mild)

Case 1
Diagnosis
• Acute hepatitis with spotty necrosis and focal
confluent necrosis
• In keeping with autoimmune hepatitis

Autoimmune Hepatitis - Acute Presentation
Incidence & Diagnostic Criteria
30- 40% of cases present as acute hepatitis /acute liver failure
(Czaja & Freese 2002, Lohse 2011)
Increasing prevalence of AIH as a cause for acute liver failure
(Fujiwara 2011)
• ? May reflect improved recognition
Autoantibodies unreliable in the diagnosis of acute AIH
• Autoantibodies and hypergammaglobulinaemia may not be present at the time
of presentation with acute AIH (Lohse 2011)
• Autoantibodies present in up to 40% of patients with other causes of acute
liver failure - e.g viral or drug-induced (Bernal 2007, Reuben 2010)

Autoimmune Hepatitis - Acute Presentation
Histological Features
Acute presentation of chronic liver disease
• 14-35% have features of chronic hepatitis (Fujiwara 2011,
Yasui 2011)
• 10-95% have bridging fibrosis or cirrhosis (Nikias 1994,
Burgart 1995, Miyake 2010, Fujiwara 2011)

Autoimmune Hepatitis - Acute Presentation
Histological Features
Acute hepatitis (with no signs of chronic liver disease)
(Hofer 2006, Te 1997, Singh 2002, Hofer 2006, Ichai 2007, Miyake 2010, Fujiwara 2011,
Stravitz 2011, Susuki 2011, Yasui 2011)
– Classical features of acute lobular hepatitis
– Mainly centrilobular distribution (central perivenulitis)
• Often associated with centrilobular necrosis
– Some cases initially have little or no portal inflammation, before
subsequently progressing to more classical features of chronic AIH

Case 1- outcome
• Treatment with corticosteroids and azathioprine
• Prompt resolution of liver dysfunction
• Negativity of autoantibodies
• Reduction of immunosuppression
‣ mild biochemical relapse
‣ reappearance of autoantibodies

Case 2
• 67 year old Caucasian male
• 1 to 2 week history of jaundice and abdominal distension
• ALT 1011, bilirubin 220, INR 2.0
• viral serology negative
• autoantibodies negative, immunoglobulins normal
• US scan
‣ small liver
‣ ascites ++
‣ spleen not enlarged
• Diagnosis: aetiology and severity
‣ acute seronegative hepatitis
‣ severe (small liver with ascites)
‣ poor prognosis for recovery
• Liver biopsy

Case 2
LIVER BIOPSY

Liver Biopsy – Case 2
Histological Findings
• Recent panacinar necrosis (multi-acinar necrosis)
– Periportal ductular reaction
– No surviving hepatocytes
Comment
• Likely to be a manifestation of severe acute hepatitis
• No obvious aetiological pointers

Case 2 – outcome
• Mild encephalopathy 1 week post-admission
• Listed “superurgent” for transplantation
• Transplanted
• Excellent recovery
‣ no early recurrence
• Continues immunosuppression

Case 2
HEPATECTOMY SPECIMEN

Case 2. Macroscopic Appearances
Shrunken liver, weight 700g. Wrinkled capsular surface

Case 2
Macroscopic Appearances

Could this be cirrhotic?

Recent Post-Necrotic Collapse versus Longstanding Fibrosis
Use Of Connective Tissue Stains
Stain
Material
Demonstrated
Distribution In
Normal Liver
Changes In Liver Disease
Reticulin
Type III collagen
fibres
Portal tracts,
hepatic sinusoids
Collapse of reticulin
framework in areas of
recent liver cell necrosis.
(few days)
Haematoxylin
Van Gieson
Type I collagen fibres
Portal tracts, walls
of hepatic veins
Increased in hepatic fibrosis
(weeks/months)
Orcein Elastic fibres Portal tracts,
walls of hepatic
veins
Found in long-standing
fibrosis/cirrhosis
(months/years)

Other Changes Seen in Areas of Parenchymal Necrosis
Congestion
May suggest a vascular problem – e.g. venous outflow obstruction

Other Changes Seen in Areas of Parenchymal Necrosis
PAS-diastase CD 68
Ceroid Pigment Laden Macrophages

Hepatectomy Specimen – Case 2
Histological Findings
• Large areas of panacinar necrosis (multi-acinar necrosis)
– Periportal ductular reaction
– Inflammation of hepatic veins
• Surviving areas of liver parenchyma
– Nodular regeneration
– Severe bilirubinostasis
– Zonal/bridging necrosis
– Little inflammation

Diagnosis
Hepatectomy Specimen – Case 2
• Severe acute hepatitis with multiacinar necrosis
(submassive hepatic necrosis)
• No strong aetiological pointers ( “seronegative
hepatitis”)

Role of Liver Biopsy in Acute Hepatitis
• Many of the classical morphological studies of acute hepatitis were carried
out before the main causes had been discovered
• Most cases of acute hepatitis now diagnosed on the basis of clinical,
biochemical and serological findings and liver biopsy is rarely indicated
• Liver biopsy may still be carried out in cases where the clinical presentation
is atypical or the cause is uncertain
– Confirm diagnosis of acute hepatitis
– Determine disease severity
– Identify possible aetiological factors (including cases of acute liver injury not
related to hepatitis)

Liver Biopsy in Acute Hepatitis
Histological Approach
1. Is this acute or chronic damage?
• severe acute hepatitis versus
• decompensated chronic liver disease
• acute exacerbation of chronic liver disease (e.g. autoimmune hepatitis,
hepatitis A/E superimposed on underlying cirrhosis)
2. How severe is the damage?
3. What is the cause?

Acute versus Chronic Damage
Severe Acute Hepatitis (e.g. case 2)
• Areas of bridging necrosis & nodular regeneration can resemble changes occurring
in cirrhosis
• Areas of multiacinar necrosis can resemble inflamed fibrous septa in cirrhosis
Acute versus Chronic Damage - Helpful pointers
• Clinical context
• Identification of normal vascular relationships
• Use of connective tissue stains to determine age of lesions

Liver Biopsy in Acute Hepatitis
Histological Approach
1. Is this acute or chronic damage?
2. How severe is the damage?
3. What is the cause?

Liver Cell Death in Acute Hepatitis
Pattern of Cell Death
Histological Features
Spotty necrosis
Apoptosis of individual hepatocytes (acidophil bodies)
Confluent necrosis
(zone 3)
Bridging necrosis
Panacinar necrosis
Loss of groups of adjacent liver cells
Confluent necrosis linking vascular structures
(central-central or central-portal bridging)
Loss of hepatocytes in an entire acinus
Multiacinar necrosis
Panacinar necrosis involving several adjacent acini
• Apoptosis > necrosis (in mild forms)
• Severe necro-inflammatory lesions uneven in distribution
‣ Sampling variability in liver biopsies
‣ Extent of hepatocyte necrosis predictive of poor outcome in some studies (Katoonizadeh
2006, Miraglia 2006, Rastogi 2011)

Liver Biopsy in Acute Hepatitis
Histological Approach
1. Is this acute or chronic damage?
2. How severe is the damage?
3. What is the cause?

Acute Hepatitis - Common Causes
1. Viral
• Hepatitis viruses – A,B,C,D, E
• Other viruses – e.g. CMV, EBV
2. Drugs
3. Autoimmune
4. Unknown
• Seronegative hepatitis (“non-A, non-B, non-C hepatitis”)
• Accounts for 40% of patients in the U.K presenting with
severe acute hepatitis leading to acute liver failure (Ichai 2008,
Bernal 2010)

Acute Hepatitis - Aetiological Considerations
Liver biopsy rarely identifies a previously unsuspected aetiology
• Biopsies mostly obtained from people in whom main recognised causes have been
excluded (“seronegative hepatitis”)
• Biopsy sometimes provides pointers to a previously unsuspected aetiology
Aetiology
Suggestive Histological features
Drugs • Disproportionately severe / well-circumscribed necrosis
(relatively little inflammation – lobular and/or portal)
• Unusual patterns of necrosis - e.g periportal (zone 1) necrosis
• Unusually prominent cholestasis
• Eosinophils, granulomas
Autoimmune
hepatitis
(Abe 2007, Fujiwara 2008,
Stravitz 2011, Yasui 2011)
• Plasma cell rich portal infiltrate (also seen in hepatitis A)
• Prominent periportal inflammation (interface hepatitis)
• Lymphoid aggregates
• Prominent centrilobular inflammation (“central perivenulitis”)

Acute Hepatitis - Aetiological Considerations
Liver biopsy may identify a cause of acute liver injury not due to acute hepatitis
• Decompensated chronic liver disease (e.g. Wilson’s disease)
• Another cause of acute liver damage (e.g. ischaemic hepatitis, severe
alcoholic hepatitis, paracetamol toxicity)
• Hepatic infiltration (usually lymphoma, less commonly carcinoma)
– Liver usually enlarged

Saturday 22 October 2011