LIVER, PANCREAS & BILIARY TRACT

Lecture No. 1
John O’Dowd

Outline of Lectures
• 1 Liver structure, function, investigation, patterns of damage
• 2 Liver failure (acute and chronic=cirrhosis). Jaundice and cholestasis
• 3 Acute and chronic hepatitis
• 4 Alcohol & NAFLD, hereditary haemochromatosis (HFE), autoimmune
disease, cirrhosis
• 5 Gall stone disease and pancreatitis
• 6 Tumours & miscellaneous

Lecture No. 1 – Learning Objectives

 To revise the structure and function of the liver
 To learn how liver disease is investigated (blood tests, imaging, biopsy)
 To undertand the significance of different patterns of abnormal liver blood
tests
 To appreciate the different patterns of damage to the liver
 To understand the concept of cirrhosis

Overview of Liver & Biliary Diseases

 Liver disease – relatively uncommon reason for morbidity/mortality in
hospital, managed by medical (gastroenterology/gastroenterologist with a
special interest in hepatology or specialist hepatologist)
o 5 deaths/100,000 approx (<1% of total deaths)
 Comparison: circulatory disease 600/100,000, cancer
200/100,000, accidents/suicide 50/100,000
o Alcohol most important aetiology for liver disease
o Other aetiological factors: viruses, metabolic (hereditary iron
overload, non-alcoholic fatty liver disease associated with tendency
to high lipids/obesity), drugs, auto-immune disease, secondary to
biliary disease, vascular
 Gall stones – relatively common, surgical. Assessed in surgical out-
patient, more rarely acute disease, typically elective surgery
 Acute pancreatitis – acute abdomen, hence managed by surgeons.
 Commonest GP problems with liver disease: abnormal liver blood test
(LFT), less often jaundice
 Tumours – metastases commonest liver tumour by far, pancreatic cancer
relatively common
 Developing countries very different pattern of liver disease - chronic viral
 disease, primary liver cancer

Liver Structure
– 1.5kg, situated right hypochondrium, 4 anatomical lobes (R>L, smaller
caudate & quadrate lobes, caudate lobe separate drainage into IVC)
– Large functional reserve, therefore significant degrees of chronic damage
can co-exist with relatively well-preserved function (“compensated” state)
– “Stable” cell population
• Little turnover normally, but…
• Capable of regeneration after insult (e.g. after partial hepatectomy)
– Limited repertoire of responses to both acute and chronic injury (that is,
different aetiological factors may produce similar patterns of response),
hence importance of history and investigations
– Different causes of liver injury may interact with/potentiate each other
Blood supply – dual supply, therefore relatively resistant to ischaemia
– Hepatic artery: 25% flow into liver, 50% oxygen supply
– Portal vein: 75% flow into liver, drains blood from gut (“splanchnic
circulation”) and spleen, rich in nutrients, more oxygen than systemic
venous blood

Venous drainage
– Hepatic vein to IVC to right ventricle

Histological structure of liver:

Plates of hepatocytes (liver cells) separated by sinusoids (blood spaces –

equivalent to capillaries elsewhere)

– Blood flows from portal vein and hepatic artery branches into smaller portal
venules and hepatic arterioles, then through sinusoids to hepatic venules,
which then join up into hepatic vein branches, then into hepatic vein

Sinusoids lined by fenestrated endothelium (i.e. endothelium with windows/gaps)

& macrophages (specialised macrophages are called Kupffer cells in the liver)

– Blood can circulate via these fenestrations into space between the
sinusoids and hepatocytes (space of Disse), allowing direct
contact/exchange between blood and hepatocytes

– Space of Disse also contains hepatic stellate cells (cells of Ito)

– Connective tissue origin, demonstrated to have central role in
fibrosis/repair in liver, that is, in development of cirrhosis
– Cells of Ito store fat and vitamin A (vitamin A overdosage causes acute
liver failure, but this is extremely rare)
Bile drainage
• Bile formed by hepatocytes
• Secreted into canaliculi between hepatocytes
• Small ductules form from canaliculi, ducts form from ductules
• Ducts join together to form left and right hepatic ducts
• Left + right hepatic duct join to form common hepatic duct
• Common hepatic duct is joined by cystic duct = Common bile duct
• 75% of people: CBD joined by pancreatic duct at ampulla
• Gall bladder used as storage pouch for bile between meals
Portal tracts
– Contain smallest branches of portal vein and hepatic artery and
interlobular (smallest) bile duct, grouped together and surrounded by
connective tissue
– Normally demarcated sharply from surrounding liver parenchyma (this
demarcation described as an ‘interface’) which contains hepatocytes,
sinusoids and hepatic vein branches

Review picture of normal liver histology in order to orientate yourself

Liver Micro-anatomy

Two competing concepts developed to describe liver architecture and help

understand patterns of damage. Acinus now the favoured concept

• Lobule – Described as being centred on hepatic vein branch, with portal tracts
at edges of each lobule. Now largely abandoned as inadequate to explain
patterns of damage. However, may still encounter descriptive terms derived
from this concept (e.g. centrilobular to refer to the area nearest the hepatic
vein branch)

• Acinus - Currently favoured idea, described as being centred on portal tracts

(blood supply), with the hepatic vein branches at periphery of each acinus.
Therefore:
– Acinar zone 1 nearest portal tract
– Acinar zone 3 furthest from portal tract & therefore from blood supply
– Most susceptible to hypoxia (e.g. if shocked/hypotensive)
– Most susceptible to oxidant drug injury (e.g. by paracetamol o/d)

• Terminology for distribution/pattern of damage/fibrosis in the liver that is used

by pathologists in their descriptions derives from which of these models is
used. The acinar model is preferred.

Review diagram of liver micro-anatomy in pathology textbooks

Liver Functions
– Synthesis of plasma proteins - albumin, clotting factors (except F8) and
fibrinolytic proteins, acute phase proteins (e.g. C-reactive protein [CRP],
serum amyloid A [SAA], ferritin), complement proteins, transport proteins,
protease inhibitors (e.g. alpha-1-antitrypsin). Synthesises most plasma
proteins apart from immunoglobulins

– Bile formation, which has two elements:

– Excretion - bilirubin, cholesterol, copper, some drugs
– Bile salts – digestion/absorption of fats and fat-soluble vitamins (ADEK)

– Detoxification - endogenous compounds (including nitrogenous

compounds such as ammonia) and exogenous compounds (including drugs
from systemic circulation and substances in portal venous blood from the
bowel, many produced by bowel bacterial action on gut contents)

– Intermediary metabolism - fat, carbohydrate, proteins absorbed from gut,

processed or stored by liver – liver important for homoeostasis

• IN BOTH DETOXIFICATION AND INTERMEDIARY

METABOLISM, LIVER FUNCTIONS AS BUFFER BETWEEN
GUT AND BODY
– Immune

– Storage: both normal (glycogen, copper, vitamins) and abnormal (iron in

excess, abnormal metabolic products in in-born errors of metabolism)

– Haemopoiesis (important in foetus/infant)

Investigation of Liver Disease – Blood Tests, Imaging,

Biopsy
Typical presentations of liver disease:
 Abnormal blood tests done either for screening or for non-specific/vague
symptoms (such as anorexia, malaise, fatigue)
 Jaundice
 Symptoms associated with chronic cholestasis (e.g. pruritus)
 Decompensated cirrhosis/chronic liver disease
 Acute liver failure

History and examination important – if there is liver disease, is it acute or

chronic? What is the cause? Are there signs of chronic liver disease? Is there
any abnormality in abdominal examination (liver, spleen, ascites)? Is there
jaundice?

Blood Tests can assess:

 Liver function – transport and excretion or protein synthesis
o Bilirubin – a sufficient rise produces clinical sign of jaundice
o Clotting time (PT) – clotting factors have a short half life, so degree of
acute damage assessed from elevation of prothrombin time due to
deficiency of clotting factors. Potential contributory role of vitamin K
malabsorption may be assessed by response to vitamin K injection
o Albumin - long half life, low level indicates chronic damage, remember
other causes of low albumin (nephrotic syndrome, protein losing
enteropathy, malnutrition)
 Liver cell damage – transaminase enzymes AST and ALT
 Liver cell reaction to bile obstruction (bile obstruction = cholestasis):
o Alkaline phosphatase, gamma-glutamyl transferase (GGT)

Additional blood tests help to clarify cause of liver disease:

 Viral serology (HAV, HBV, HCV,EBV)

 Immunological reaction or evidence of injury
o Presence of auto-antibodies, immunoglobulin levels
 Iron storage status (ferritin, iron, %saturation of transferrin), molecular genetic
testing for haemochromatosis (see Haemochromatosis)

 Biochemistry lab: standard liver profile is AST, ALT, Alk Phos, GGT,
bilirubin, albumin
 PT: done in haematology lab using a coagulation blood tube
 Liver blood tests are often called liver function tests (LFTs) even though
not all of them assess function.

Remember concept of normal range for laboratory blood tests = based on

distribution of values in a population, norma;l range defines values lying within +/-
2 SDs of mean value for a population. Implies 2.5% of people with values above
normal range on random testing of a population.
Modern biochemistry analysers may test for many different analytes on one
sample. Therefore, if 20 separate tests done in a test panel, 64% chance that
one test at least will have value above normal range.

Always assess blood test results critically:

 Outside range doesn’t necessarily mean clinically abnormal

 Within normal range doesn’t always exclude clinical disease
Bilirubin
 Normal <18-20umol/l, clinical jaundice appears if >50umol/l
 In between, bilirubin levels abnormal = “biochemical jaundice”
 Elevation may reflect liver, biliary or non-liver disease (i.e. haemolysis):
see Jaundice
 Isolated mild elevation may be Gilbert’s syndrome if haemolysis excluded

Aspartate transaminase (=SGOT)

– Present in liver, heart, muscle, levels rise if these tissues damaged

Alanine transaminase (=SGPT) - more liver-specific than AST

– AST & ALT – elevation sensitive for indicating presence of

hepatocellular damage but poor correlation of level of elevation with
extent of damage or prognosis
– AST:ALT >2.0 (that is, disproportionate AST rise compared to ALT)
suggests alcohol as aetiology of injury (especially in early stage disease)
as most other liver diseases have AST:ALT <1.0. Normal values of AST
usually < normal values of ALT.

 Causes of elevated transaminases: liver injury from viruses, alcohol, drugs

(e.g. NSAIDs, antibiotics, statins, antiepileptics), metabolic diseases (e.g.
NAFLD), autoimmune disease, vascular congestion,
ischaemia/hypotension
 Very high transaminases (>1000) typically caused by acute viral infection,
drugs or ischaemia/hypotension.
 But remember clinically silent non-liver causes of elevated transaminases:
muscle injury (?CK), coeliac disease, thyroid disease, anorexia nervosa,
adrenal insufficiency.
 Transaminases may be in normal range despite significant liver
damage/fibrosis

Alkaline phosphatase
Locations:
 Hepatocyte membrane, adjacent to bile canaliculi
 Bone osteoblasts: increased in childhood/bone growth and diseases with
increased bone turnover (Paget’s disease, bone metastases but NOT
myeloma which causes purely lytic lesions in bone, therefore no elevated
alk phos)
 Placenta: increased in pregnancy

Hepatocytes sensitive to obstruction of bile flow (whether just local or more

global throughout liver). Obstruction stimulates hepatocytes to leak alkaline
phosphatase into blood

Gamma glutamyl transferase (GGT)

– Present in liver cells, blood levels sensitive to obstruction
– Elevation also induced by alcohol, some drugs (anticonvulsants,
warfarin)

Elevated alkaline phosphatase plus elevated GGT suggests hepatobiliary

disease
Whereas, elevated alkaline phosphatase alone raises the alternative possibility of
bone disease (consider ?pregnant or ?adolescent).
Main use of GGT is to refine assessment of alkaline phosphatase abnormalities.

Patterns of abnormal liver blood tests

Rise AST/ALT > rise alk phos/GGT = hepatocellular pattern

Rise alk phos/GGT > rise AST/ALT = obstructive or cholestatic pattern

 When assessing liver blood tests, the pattern of abnormality is significant -

which markers are elevated and which are normal, hepatocellular versus
obstructive
 Remember that abnormal liver blood tests are not necessarily specific for
liver disease and that not all liver disease is manifested by abnormal liver
blood tests
 Always interpret liver blood tests in the clinical context

Abnormal liver blood tests developing in a hospitalised patient (no previous

known liver disease), consider drugs, ischaemia/hypotension, sepsis as causes.

Particularly complex situations may include patients post-operative, post-solid

organ or BM transplant, ICU, TPN, HIV/AIDS, complicated sickle cell disease

Management of single isolated abnormal liver blood test:

 “Clinical filter”
o Does the patient have any risks for, symptoms or clinical features of
liver disease?
o Was the test just done to assess a non-specific illness or as a
screening test?
 Scale of elevation?
o Just “out of range” – repeat after interval, interval of a few months
reasonable if considering possible liver disease (progresses slowly)
o Greater than several times upper limit of normal – more likely
pathological (exception isolated elevation GGT)
 Transient or persistent?
Initial work-up of non-urgent liver blood abnormalities – history and exam (risks,
alcohol, medications, ?DM/obesity/lipids), viral serology, iron storage status, liver
autoimmune screen & ultrasound
Imaging

 Ultrasound - easy, portable, no radiation

o Questions answered by US: Liver normal size or shrunken, bile ducts
normal or dilated, stones present in gall bladder, liver texture (fatty,
cirrhotic or not), focal lesion(s) present, if so solid or cystic
o Ultrasound signal impeded by bowel gas – lower end CBD behind
duodenum not well visualised – can miss common bile duct stones
 MRCP = magnetic resonance choledocho-pancreatography
o Can image lower end of CBD well – limited by availability
 CT – radiation exposure, similar information to US
 Endoscopic ultrasound (EUS) – skill dependent, can visualise CBD well
 ERCP = endoscopic retrograde choledocho-pancreatography
o Diagnostic: provides retrograde image of biliary and pancreatic tract
o Therapeutic: can remove stone or place stent across a stenosis
o If MRCP +/- EUS available, pure diagnostic use rare, generally done
only if therapeutic procedure also considered (i.e. likely obstructive
dilatation of CBD)
 PTC = percutaneous transhepatic cholangiography
o Used if impossible to access obstructed duct system from below

Liver biopsy possible approaches

– Percutaneous needle (usual) – radiologist (US guidance) or gastro-
enterologist (less often nowadays)
– Transjugular needle (esp. if clotting problem)
– Laparoscopic needle or wedge (esp. if focal subcapsular lesion)

Indications:
 Diffuse liver disease
o Diagnosis? Extent/progression (especially of chronic damage)?
o Getting rarer – only if treatment decision informed by result (?only
30% of biopsies), balance of risks/benefits needs to be considered
 Diagnosis of local lesion (may be US or CT guided) ?nature of lesion
 Local lesions may also be sampled using fine needle aspiration cytology
 Liver manifestation of systemic disease (e.g. in pyrexia of unknown origin
looking for TB), very rare indication

 Risks of liver biopsy - bleed, bile leak, trauma (lung)

 C/I to liver biopsy - clotting problems, biliary obstruction – always check
clotting function/platelets before biopsy, group & screen blood
 Low but defined mortality of liver biopsy (<0.5/1000)

Liver biopsy goes to histopathology laboratory

Routine H&E stain done on liver biopsy, but also: special stains done on all liver
biopsies for fibrosis (Masson’s trichrome), iron (Perls’; stain)

Damage to the Liver

Acute – depends on degree of damage and whether transient or
persistent/repeated, possible outcomes are recovery, death or (if continued
insult) chronic disease.

– Liver has regenerative capacity, so recovery (restitution back to normal)

possible if damage transient. However, massive acute injury may be
overwhelming despite large functional reserve of normal liver, causing
fulminant (acute) hepatic failure and possibly death

Chronic – continuing/repeated insult, leads to fibrosis

– Connective tissue framework damaged, complete recovery (restitution to

normal) no longer possible, fibrosis by hepatic stellate cells stimulated

Cirrhosis = name given to end-stage chronic liver disease following

ongoing chronic damage, structural equivalent to functional state of chronic
hepatic failure
 Diffuse, extensive change to liver architecture
 Characterised by bands of fibrous tissue separating regenerative nodules
of liver cells
 Key functional consequence of cirrhosis is that normal vascular
relationships disturbed, portal blood not processed, portal hypertension
develops
 Classical idea – cirrhosis fixed, irreversible. Now recognised as dynamic/
evolving, so lots of current interest in therapeutic approaches to stopping
progression of fibrosis or even reversing fibrosis

Different causes of liver damage may interact synergistically (e.g. alcohol

with hepatitis C virus or haemochromatosis with alcohol or alcohol increasing
susceptibility to paracetamol overdose)
PATTERNS OF CELL DAMAGE/DEATH
In levels of increasing severity (different triggers/different degrees):
– Damaged cells swell (‘balloon’), damage may be reversible or may be
irreversible and proceed to cell death
– Single cells may die one-by-one by apoptosis
– Seen on biopsy as small intensely pink cells with shrunken pyknotic
nuclei (=Councilman bodies, eponym given to these apoptotic
hepatocytes when identified in acute viral hepatitis)
– Small coalescent groups of cells may die (described as ‘spotty necrosis’
when seen on biopsy)
– Large confluent groups of cells may die (called ‘bridging’ necrosis when
seen on biopsy)
– May form ‘bridges’ of necrotic hepatic parenchyma between portal
tracts or between portal tracts and central veins
– Massive hepatic necrosis = leads to acute/fulminant hepatic failure

PATTERNS OF INFLAMMATION
 Inflammatory cells may be in parenchyma (a distribution described by
pathologists as ‘lobular’) and/or portal tract/periportal (‘portal’) areas.

 Primarily portal inflammation may spill over the normally-sharp interface

between portal tract and parenchyma (causing interface inflammation)
 “Piecemeal necrosis”
Specific pattern of chronic injury (see Chronic hepatitis) occurring
when portal tract inflammation spills over the interface to involve/
damage adjacent hepatocytes, classically seen in chronic hepatitis B
or autoimmune hepatitis

 Inflammatory cells in hepatitis usually lymphocytes (as in viral or auto-

immune hepatitis), no matter whether the clinical pattern is of acute or
chronic disease
 Neutrophil polymorphs in liver inflammation are relatively unusual but
suggest alcohol damage or its mimics (NAFLD)

Definitions

Hepato = to do with liver

Chole = to do with bile/biliary tract
Choledocho = to do with bile duct
Cholecysto = to do with gall-bladder
Retrograde = opposite to the physiological direction of flow (in the direction of
physiological flow is antegrade)
Endoscopic = via an endoscope
Percutaneous = through or via the skin

Lecture 1 - Key Revision

 What are the important functions of the liver?
 Be able to assess the results of a routine liver blood test profile critically
 How do blood (biochemical) tests distinguish between damage to hepatocytes
and obstruction to bile flow?
 What are the causes of an elevated alkaline phosphatase?
 What information does a rise in GGT add?
 What use are albumin and prothrombin time in assessing liver disease?
 What is cirrhosis?
 Revise overview of liver and biliary diseases

• Lecture series on diseases of liver, pancreas and biliary tract prepared April
2011 by:
• John O’Dowd, Department of Pathology, Royal College of Surgeons in Ireland,
Education and Research Centre Beaumont Hospital
• Any suggestions, comments or corrections on these notes welcome on email
• email address [email protected]

LIVER, PANCREAS & BILIARY TRACT

Lecture No. 2
John O’Dowd

Lecture No. 2 – Learning Objectives

•To understand acute/fulminant hepatic failure and know the common cause
•To understand hepatic encephalopathy & know how it arises
•To know how cirrhosis presents and what is meant by decompensated/
complicated cirrhosis
•To understand the causes and significance of portal hypertension, ascites &
varices
•To be able to classify jaundice rationally
•To understand cholestasis and its causes & effects

Fulminant Hepatic Failure (=Acute Liver Failure)

Severe acute damage to previously healthy leading to rapid development of:
 Impaired synthetic function
  Hepatic encephalopathy (which is clinically obvious), typically defined as
HE arising within 8 or 12 weeks of first indication of liver dysfunction

Causes:
Acute damage due to drugs, especially paracetamol
Acute damage due to viruses, rare outcome of acute hepatitis A or B

Massive hepatic necrosis, similar patterns of damage irrespective of cause

Rare causes: Reye’s syndrome in children, Wilson’s disease, other childhood

metabolic causes, Budd-Chiari syndrome (IVC/hepatic vein occlusion), toxic
mushroom poisoning, pregnancy-associated (see lecture 6)

 Hepatic/liver failure may be described as fulminant/acute or

subfulminant/subacute or classified by interval between onset of first
symptoms and onset of failure. However, prognosis of all is poor
 Up to 80% mortality overall
 Artificial hepatic assist device (liver equivalent of kidney dialysis) difficult to
develop because of complexity of liver function
 Early consideration of listing for transplant

By definition, exclude chronic disease – acute presentation of decompensated

cirrhosis may appear very similar but has different clinical course & management
(portal hypertension & ascites typically absent in fulminant/acute hepatic failure)

Effects of acute/fulminant hepatic failure

 Hepatic encephalopathy (defining characteristic: see below for description

may also be a/w decompensated cirrhosis)
 Cerebral oedema - raised intracranial pressure, commonly cause of death
 Clotting problems (degree of abnormality guide to prognosis)
 Acute renal failure (type 1 hepatorenal syndrome) – exclude direct toxicity,
sepsis, drugs as cause
 Metabolic acidosis
 Hypoglycaemia
 Infection – altered immune function, especially related to handling of gut
bacteria transiently present in portal blood

Hepatic Encephalopathy
(=Portasystemic Encephalopathy, PSE)
 Neuropsychiatric syndrome, which is potentially reversible, associated
with impaired hepatic function.
  May occur as a result of acute/fulminant hepatic failure or as a feature of
decompensation in a/w cirrhosis (equivalent to chronic hepatic failure with
in addition porto-systemic shunting of blood)
 In cirrhosis, may occur spontaneously a/w progressive decline of function
or may be precipitated
 May resolve spontaneously or with removal of precipitant +/- active
treatment or may persist (as in FHF if liver not transplanted) or may recur.
 Spectrum of changes from subtle to clinically overt to profound.
 Affects level of consciousness, intellectual function, personality and
behaviour, neuromuscular function (e.g. reflexes, tremor, flap = asterixis)
 May be subtle (minimal HE) – early in fulminant hepatic failure or as
background finding in chronic liver disease – e.g. altered personality,
sleep disturbance
 Exclude other metabolic or neurological conditions causing similar
changes, e.g. intracranial lesion, trauma [subdural haematoma], infection,
epilepsy, chronic alcohol effects

HE caused by functional disturbance in brain (minimal structural effects).

Cirrhosis typically associated with portal hypertension and distorted vascular
relationships – i.e. shunting of ‘unprocessed’ portal and arterial blood through
liver, bypassing hepatocytes – as well as reduced function
Reduced hepatic function (acute or chronic): reduced detoxification/buffering
function by liver

Any therapeutic porta-systemic shunt used to decompress the portal system in

patients with portal hypertension (whether surgical or transjugular intrahepatic
porta-systemic shunt [TIPSS]) may worsen or provoke hepatic encephalopathy
as more ‘unprocessed’ portal blood reaches systemic circulation

Pathogenesis: No single cause for HE, multiple hypotheses, different elements

probably interact
 Excess ammonia (endogenous, normally detoxified by liver, formed from
protein/amino acid metabolism AND exogenous from gut bacteria)
 Altered central neurotransmission (GABA, glutamate systems) perhaps
related to bacterial products absorbed from gut
 Altered AAA:BCA (ratio of aromatic to branched chain amino acids)

Precipitants of HE (on a background of previously compensated

cirrhosis)
 Additional insult to liver (e.g. alcohol or HAV)
 GI bleed (common in cirrhosis/portal hypertension; protein load)
 Increased dietary protein (“big meal”)
 Constipation (increases protein uptake)
 Inappropriate sedation (alcohol, benzodiazepines, opiates)
 Dehydration/reduced perfusion (sepsis, hypovolaemia [e.g. diarrhoea,
vomiting, diuretics, large volume paracentesis])
  Therapeutic shunting

See: therapeutics of fulminant hepatic failure/hepatic encephalopathy

Chronic Liver Disease

Advanced chronic liver disease implies cirrhosis (=chronic liver failure)

Cirrhosis is the structural state that is equivalent to the functional state of chronic
liver failure or end-stage chronic liver disease.

Cirrhosis typically associated with portal hypertension and ascites, risk of

hepatocellular carcinoma, risk of decompensation (variceal bleed, HE, ascites +/-
SBP, HRS)

Cirrhosis causes circulatory alterations: vasodilatation of splanchnic (gut) blood

supply, increases flow through portal veneous system, raises portal pressures,
decreases systemic total peripheral resistance, reflex rise in cardiac output
(=”hyperdynamic circulation”), vasoconstriction of renal blood supply, decreased
renal perfusion, thus triggering renal-angiotensin-aldosterone system

Cirrhosis may present with

 Classic clinical signs of chronic liver disease
 Incidental discovery on liver blood tests or radiology (low albumin key hint
of chronic disease) but patient stable
 Complicated disease (=decompensated) disease: ascites, HE, variceal
bleed, SBP, HRS
 At autopsy

Remember: despite modest/few clinical symptoms/signs and/or modest/absent

biochemical abnormality, cirrhotic liver has reduced or absent functional reserve.
In an unstressed state, the residual function may be enough to avoid overt
symptoms or signs (=compensated disease). However, a further progression of
disease or additional (potentially minor) stress or insult may trigger
decompensation

This is a paradigm for all chronically damaged systems/organs with limited

functional reserve and their susceptibility to further acute damage.

Clinical Signs of Chronic Liver Disease

 Failure of hormone (oestrogen) inactivation by liver: testicular atrophy,
gynaecomastia, palmar erythema, spider angiomas [naevi] – latter two also
associated with pregnancy
 Hepatomegaly (nodular, but liver more typically shrunken in advanced
cirrhosis)
 Splenomegaly
 Ascites
 Muscle wasting
 Hyperdynamic circulation
 Jaundice (depends on cause of cirrhosis more than severity, may be very
late/absent)
 ?Presence of minimal (subclinical) hepatic encephalopathy

Major Complications of Cirrhosis

 Portal hypertension, with risk of variceal haemorrhage
 Ascites
 Spontaneous bacterial peritonitis arising on background of ascites
 Hepatic encephalopathy
 Hepatorenal syndrome (type 2, background of chronically reduced renal
perfusion)
 Risk of hepatocellular carcinoma (in 3% of cases with cirrhosis/year)
 Clotting abnormalities
 Risks associated with surgery (infection, bleeding, healing, ascites)
 Caution with therapeutic drug treatment

Ascites, variceal bleeding, HE, HRS, SBP = decompensated cirrhosis

Cirrhosis will be addressed again in lecture 4: classification of cirrhosis, prognosis,

diagnosis, treatment

Portal Hypertension
Normal portal venous system is a low pressure system
Pathogenesis in cirrhosis:
 Increased resistance to flow in cirrhotic liver
 Cirrhosis causes increased portal blood flow which maintains and worsens
portal hypertension

Classified by level/site of origin for portal hypertension

Commonest cause is cirrhosis

Consequence of portal hypertension is that portal blood flows into systemic

circulation without processing (i.e. background for hepatic encephalopathy):
  Blood flow altered in liver as blood shunted through intra-hepatic collateral
channels that open up, bypassing hepatocytes, leading to loss of function
 Portal hypertension also causes extra-hepatic collateral anastomoses with
systemic veins to open up to decompress portal system, again portal
blood bypassing liver with added risk of bleeding
 Same effect by therapeutic porta-systemic shunts (surgical or TIPSS)

Classification of Portal Hypertension

Pre-hepatic obstruction to flow - portal vein thrombosis, rare
o Secondary to septic and thrombotic states, tumour
o Historically commonest cause: acute appendicitis or neonatal umbilical
sepsis spreading to portal vein with secondary portal vein thrombosis
Hepatic (intra-hepatic) site of origin of portal hypertension
 Cirrhosis – COMMONEST cause overall by far
 Portal tract fibrosis without cirrhosis
o Schistosomiasis (fibrotic reaction to schistosome eggs in PV branches)
 Veno-occlusive disease (fibrosis of central venules, rare phenomenon a/w
chemotherapy, GvHD, radiotherapy, toxins)
Post-hepatic obstruction to flow
o Acute hepatic vein/IVC thrombosis = Budd-Chiari syndrome
Very rare cause of fulminant hepatic failure with prominent portal
hypertension. May be associated with thrombotic states, Pill,
pregnancy, tumour or spontaneously occurring

Consequences of Portal Hypertension

 Collaterals open up between portal and systemic vein branches
o Varices (oesophageal and gastric) – MOST IMPORTANT collateral
channels
o Retroperitoneal, rectal, peri-umbilical collaterals also develop (peri-
umbilical collaterals cause rare clinical sign of ‘caput medusae’)
 Shunting of blood past liver: reduced liver function, susceptible to hypoxia,
increases susceptibility to decompensation of liver function (e.g. HE)
 Ascites: ascites in cirrhosis always associated with portal hypertension
 Splenomegaly secondary to congestion, may cause low blood counts
Varices
30% of patients with varices bleed, of whom 30% die, high rate of recurrence
In alcoholics – remember: not all upper GI bleeds are varices

 Management of acute bleed: resuscitate, prevent/treat complications

(aspiration, HE, ARF), diagnose cause of bleed (endoscopy) and treat cause
of bleeding
o Drug treatment (octreotide, vasopressin)
o Endoscopic treatment (banding of varices)
o If failure to control - temporary stabilisation with balloon tube
tamponade (compression with Sengstaken-Blakemore tube)
 o Decompression by shunting for failed treatment or recurrent bleeding
(surgery or TIPSS
 Secondary prevention: prevent re-occurrence – propranolol, banding
 Primary prevention: varices identified, prevent initial bleed (as above)

See: therapeutics/management of acute upper GI bleed/oesophageal

varices/acute variceal haemorrhage

Ascites
Defined as fluid in peritoneal cavity
May be tense, uncomfortable
Causes of ascites: remember fluid collections can be exudates or transudates
 >80% cirrhosis (rarely other liver disease e.g. Budd-Chiari) –
always associated with portal hypertension
 10% malignancy - classic presentation advanced ovarian cancer
 5% heart failure
 <5% others (TB, dialysis)

Occurs in cirrhosis in association with portal hypertension = worsening prognosis

Aetiology: haemodynamic effects of cirrhosis on kidney (renal vasoconstriction),

causes rennin-aldosterone activation, salt and water retention, preferentially
located as ascites in the context of portal hypertension

Diagnosis of cause of ascites at first presentation: tap of ascites fluid

(=paracentesis), safe procedure, investigations performed:
 Microbiology including TB (remember if suspected SBP, inoculate into
blood culture bottles)
 Cell count (done in haematology bottle, >25polys/mm3 implies infection)
 Biochemistry (albumin level of ascites fluid relative to serum level)
 Cytology (?malignancy)

Treatment: salt restriction, diuretics, if diuretic-resistant, therapeutic paracentesis
to remove fluid

Spontaneous Bacterial Peritonitis (SBP)

Complication of cirrhotic ascites, early identification leads to effective treatment.
Suspect if: deteriorating patient with ascites: fever, abdominal pain or
tenderness, drowsiness.
Effective diagnosis leads to prompt, more effective treatment: low threshold for
paracentesis, do it routinely on admission for patients with cirrhosis & ascites:
send cell count, microbiology

Hepatorenal Syndrome
Acute renal failure secondary to liver disease with otherwise-normal kidneys

Type 1 – a/w acute/fulminant hepatic failure, very poor prognosis

Type 2 – a/w cirrhosis, typically in patients with ascites and similar pathogenesis
(haemodynamic effects of cirrhosis: splanchnic vasodilatation, compensatory
renal vasoconstriction, renin-angiotensin-aldosterone axis stimulated, kidney
susceptible to failing)
Exclude other causes of renal failure: drugs, infection, hypovolaemia

Onset of major complications of cirrhosis (decompensated cirrhosis) such as HE,

ascites, variceal bleed, SBP, HRS - implies much worse prognosis

JAUNDICE & CHOLESTASIS

Jaundice = Icterus, yellow discolouration of tissues by excess bilirubin (skin and
sclera, tissues with high elastin content, bilirubin binds to elastin).
‘Jaundiced’ synonymous with ‘icteric’

Clinical jaundice = bilirubin >50umol/l

“Biochemical jaundice” bilirunin >18-20<50umol/l, not clinically evident
Chronic jaundice - green colour (as bilirubin oxidised to biliverdin), slow to fade if
cause removed

Cholestasis means failure of normal bile flow. Only some causes of jaundice
due to cholestasis, whilst cholestasis causes more than just jaundice

BILIRUBIN METABOLISM
 Haem breakdown produces bilirubin
o RBCs broken down in spleen.
o RBC haemoglobin represents 75% of bilirubin; 25% myoglobin,
cytochromes etc containing haem from other tissues

 Unconjugated bilirubin is highly water-insoluble (but lipid-soluble), circulates

in blood bound to albumin
o Cannot be filtered (passed) at kidney as water-insoluble
o Can cross blood-brain barrier (as it is lipid soluble), therefore:
o High levels unconjugated bilirubin toxic, esp. to brain of fetus/neonate
– bilirubin-associated fetal/neonatal brain damage is kernicterus

 Bilirubin actively taken up by liver cell and then conjugated by liver cell with
glucuronate into water-soluble form for excretion in bile
o Conjugation efficient process, enzyme UDP-glucuronyl transferase
 o 3% of population have inherited syndrome with mildly reduced
efficiency of conjugation (Gilbert’s syndrome), harmless
o Crigler-Najjar similar inherited defect, more severe and very rare
o Conjugation much less efficient process in premature infants
o Uptake, conjugation & excretion by hepatocytes into bile canaliculi all
active enzymatic processes

 Conjugated bilirubin water soluble, excreted in bile

o If bile flow blocked, reabsorbed into blood and filtered at kidney,
therefore:
o Bilirubinuria = conjugated hyperbilirubinaemia
o Conjugated bilirubin is dark, colours urine dark if filtered at kidney
o Conjugated bilirubin of itself not toxic

 Conjugated bilirubin excreted by hepatocytes in active enzymatic process

o Very rare inherited enzyme defects may affect bilirubin excretion
(Dubin-Johnson and Rotor syndromes), generally of little or no
significance after clinical recognition

 Conjugated bilirubin oxidised in bowel to urobilinogen (gives faecal colour)

MECHANISMS OF JAUNDICE
 Excess bilirubin production (i.e. from outside liver)
o Haemolysis (intravascular or associated with dyserythropoiesis)
o Uptake/conjugation overwhelmed, unconjugated hyperbilirubinaemia

 Inherited/physiological abnormalities in uptake/conjugation/excretion

o Very rare apart from Gilbert’s syndrome or prematurity
o Both Gilbert’s and prematurity cause unconjugated hyperbilirubinaemia

 Disease of liver cells/hepatocellular disease (e.g. hepatitis)

o Whole process (uptake/conjugation/excretion) upset
o Uptake/conjugation usually very efficient processes. Whereas:

o Excretion into canaliculi is the usual rate-limiting step, upset most

therefore in damaged cells
o Swollen damaged cells may also compress bile canaliculi
o Hepatocellular disease tends to cause predominantly conjugated
hyperbilirubinaemia as excretion upset more than uptake/conjugation.
o Liver blood tests show mixed hepatocellular damage/obstructive
picture, hepatocellular damage usually predominating

 Intrahepatic cholestasis: conjugated hyperbilirubinaemia

o Liver blood tests show obstructive-predominant picture
 o May have chronic cholestatic effects in addition (e.g. pruritus)
o Disease affecting bile ducts within liver, either structural damage (PBC,
PSC, infiltrative disease) or functional effect on bile flow within liver
(e.g. drugs [chlorpromazine, OCP], pregnancy-associated cholestasis,
associated with systemic sepsis, rare inherited benign recurrent
intraheptatic cholestasis [BRIC])
o Intrahepatic structural causes must affect a sufficient number of bile
ducts within liver to give rise to hyperbilirubinaemia or jaundice
o Therefore, unless extensive, metastatic tumour or other infiltrative
diseases (e.g. sarcoidosis, lymphoma, amyloid) in liver does not
necessarily cause jaundice even if obstructive picture on blood tests

 Extrahepatic cholestasis: conjugated hyperbilirubinaemia. Caused by

obstruction outside liver: stone, tumour, stricture

CLASSIFICATION OF JAUNDICE
 By mechanism: excess bilirubin production, specific enzyme defects,
hepatocellular disease, intra- or extra-hepatic biliary tract disease +/-
cholestasis
 By site: pre-hepatic, hepatic, post-hepatic
 Biochemical (theoretical rather than clinical use generally): conjugated
versus unconjugated hyperbilirubinaemia
o Adult biochemistry laboratories don’t divide bilirubin levels into
conjugated and unconjugated fractions, obstetric/neonatal
biochemistry laboratories may report them separately

Increased bilirubin production

 Haemolysis, dyserthyrpoiesis (with formation of large amounts of abnormal
RBCs as in thalassaemia)

 Always check for haemolysis in jaundice/isolated hyperbilirubinaemia if

no other liver blood test abnormalities: FBC, blood film, reticulocyte count,
haptoglobins, LDH

 Neonate/foetus with massive haemolysis due to mother/child rhesus

incompatibility: increased bilirubin production, immaturity of hepatic
conjugation enzyme, leads to very elevated unconjugated bilirubin levels
o Unconjugated bilirubin can cross blood/brain barrier
o Brain damage associated with high levels is called kernicterus

Inherited/physiological abnormalities in uptake/

conjugation/excretion
 Neonate - low levels of conjugating enzyme, esp. if premature
o Neonatal jaundice common (unconjugated hyperbilirubinaemia),
usually mild and transient as infant matures, more of a problem with
significant prematurity with risk of kernicterus
 Inherited mildly defective conjugation, common = Gilbert’s syndrome
 Other inherited conjugation enzyme defects very rare (Crigler-Najjar)
 Inherited defects in excretion enzymes also rare (Dubin-Johnson, Rotor)

Hepatocellular disease/damage
Predominant conjugated hyperbilirubinaemia
Can be seen with any cause of hepatitis: viral, drug, alcohol, autoimmune,
metabolic although hepatitis very frequently anicteric.

Intrahepatic cholestasis

Obstruction to bile flow or failure of normal bile flow within liver

 Primary bile duct disease: PBC, PSC (see later lectures)
 Infiltrative disease within liver (metastases, lymphoma, sarcoidosis, amyloid))
 Drugs (chlorpromazine, OCP), pregnancy (rarely), sepsis, inherited BRIC: all
can have poorly understood functional effect on bile flow within liver

Extrahepatic cholestasis (obstruction)

Obstruction to normal bile flow outside liver. Used to be termed “surgical
jaundice”. Identify and treat cause (US, MRCP, EUS, ERCP)
 Common bile duct stone
 Stricture
o Post-biliary tract surgery or instrumentation
o Primary sclerosing cholangitis affecting extrahepatic bile ducts
 Tumour
o Within or at end of bile duct
o Compression from outside
 Rare – external compression from stone impacted in cystic duct (Mirizzi
syndrome), congenital abnormalities in biliary tract (choledochal cyst)
EFFECTS OF CHOLESTASIS
 Conjugated hyperbilirubinaemia
o Jaundice
o Dark urine (excess bilirubin filtered at kidney, bilirubinuria)

 Obstruction to bile flow into gut

o Pale stools (no urobilinogen made in gut to colour faeces)
o Reduced cholesterol excretion/hypercholesterolaemia
 o Chronic obstruction to bile salt excretion into gut
 Pruritus from retained bile salts
 Fat malabsorption (steatorrhoea)
 Fat-soluble vitamin malabsorption (ADEK)

Elevated alkaline phosphatase/GGT predominant – obstructive enzyme

picture
Imaging (ultrasound, MRCP, CT, EUS) critical
Are there dilated ducts? Is an extrahepatic cause of obstruction demonstrated?
Extrahepatic obstruction is a risk for ascending cholangitis.
Can the extrahepatic obstruction be treated (stone removal, stenting)?

Gilbert’s syndrome
Genetic defect in bilirubin uptake/conjugation a/w with isolated, mild elevation in
bilirubin
3% of population
Bilirbuin levels may rise more with fasting, surgery or illness and cause mild
jaundice
Importance: don’t label as chronic liver disease
Diagnosis: isolated mild rise in bilirubin (unconjugated) with other LFTs normal,
haemolysis and drug-related cause excluded

Assessment of jaundice
 Urgent referral if symptoms/signs of infection/obstruction or failure

 Do liver blood tests and FBC

 Consider haemolysis (may need haematology referral)
 Other tests (apart from bilirubin) normal: consider Gilbert’s

 Obstructive picture on liver blood tests: refer

 Picture of hepatocellular damage a/w jaundice: consider acute hepatitis A: if

acute serology positive (IgM anti-HAV positive): observe, presume to be HAV-
related; otherwise, if acute HAV serology negative, refer.

 Jaundice + low albumin = highly suggestive of chronic liver disease: refer

 May be multiple causes/possible causes of jaundice and/or liver blood test

abnormalities in some complex contexts: post-surgery, post-organ or BM
transplant, patient on TPN, patient with HIV/AIDS or sickle cell disease

 Lecture 2 - Key Revision

  What is the clinical picture of fulminant hepatic failure?
 What are the causes and effects of fulminant hepatic failure?
 What are the effects and complications of cirrhosis/chronic liver disease?
 How does portal hypertension develop and how is it classified?
 What are the consequences of portal hypertension?
 How is ascites related to liver disease? Are there other causes of ascites?
 Know the importance of hepatic encephalopathy, oesophageal varices
and spontaneous bacterial peritonitis

 What is jaundice and how does it arise?

 Be able to talk logically about the mechanisms and causes of jaundice
 Be sensible: don’t focus on rarities, know what is common
 What is cholestasis? What are its effects? How is it diagnosed?
 Compare gross and microscopic photographs of normal liver and cirrhosis

• Lecture series on diseases of liver, pancreas and biliary tract prepared April
2011 by:
• John O’Dowd, Department of Pathology, Royal College of Surgeons in Ireland,
Education and Research Centre Beaumont Hospital
• Any suggestions, comments or corrections on these notes welcome on email
• email address <[email protected]>

LIVER, PANCREAS & BILIARY TRACT

Lecture No. 3
John O’Dowd

Lecture No. 3 – Learning Objectives

 Understand acute and chronic hepatitis

 What are the causes of acute hepatitis?
 What causes chronic hepatitis?
 What is the consequence of chronic hepatitis
 How is chronic hepatitis assessed?
 Distinguish hepatitis A, B & C: transmission & chronicity
 Understand pathogenesis of HBV infection (disease pattern in adults
versus neonates)
 Understand the worldwide burden of chronic HBV and chronic HCV
infection
 Understand HBV serology: the significance of HBe and HBs antigens,
anti-HBs antibody
  Understand HCV diagnosis and disease progression

HEPATITIS
 Acute hepatitis – abnormality resolved <6/12
 Chronic hepatitis – persisting abnormality >6/12
 Some diseases cause only acute hepatitis (e.g. HAV, most drug hepatitis)
 Others by definition cause only chronic hepatitis (e.g. autoimmune,
Wilson’s)
 Some causes of acute hepatitis may become chronic (e.g. most neonatal
HBV, a proportion of adult HBV, most HCV)
 Flares/exacerbations of chronic hepatitis of any causes may mimic acute
hepatitis (clinical or biochemical)
 Many causes of chronic/acute-on-chronic liver disease have distinctive
features and not considered under the diagnostic heading “chronic
hepatitis” (e.g. alcoholic liver disease, non-alcoholic fatty liver disease,
chronic liver disease associated with primary biliary cirrhosis or primary
sclerosing cholangitis, hereditary haemochromatosis)

ACUTE HEPATITIS
Acute diffuse liver damage with inflammation
Degree of damage varies
Acute = resolution/n

ear resolution of abnormalities within six months

Causes of acute liver inflammation

 Viruses (esp. hepatotropic viruses but also EBV, CMV, rubella)
 Drugs (histology may be identical to virus)
 Steatohepatitis related to alcohol or other causes: distinctive
clinical/histological features (so usually considered separately from other
causes of “acute hepatitis”)
 Acute biliary obstruction (e.g. stone in CBD) presents distinctively:
secondary inflammation in portal tracts only (different features to acute
hepatitis, effects of obstruction more prominent)

Note: Some kinds of chronic hepatitis that have been previously clinically silent
can present in a way that mimics acute hepatitis (e.g. autoimmune hepatitis,
chronic viral hepatitis, Wilson’s). Such a presentation may allow their recognition

Symptoms
 Often silent (more often silent/anicteric in children than adults)
 May be vague/generalised symptoms: nausea, anorexia, malaise,
abdominal discomfort, joint pains
  Rare: presents with fulminant (acute) hepatic failure

Signs
 Enlarged, tender liver
 Clinical jaundice may occur but more usually anicteric (esp. in children)
 If jaundice deep/persistent, called ‘cholestatic hepatitis’
 Must have no signs/evidence of chronic disease in order to qualify for
label as “acute”

Blood tests
 High AST/ALT (transaminases, may be in 1000s) but peak levels don’t
correspond to risk of fulminant hepatic failure
 Conjugated hyperbilirubinaemia (but often not high enough to give
jaundice)
 Mild rise alkaline phosphatase/GGT (elevation less relative to elevation of
transaminases – i.e. biochemistry more “hepatitic”/hepatocellular damage
pattern rather than obstructive pattern)
 Albumin normal (because not chronic disease)
 PT time may lengthen: usually mild, correlates w/severity of acute
damage, if markedly prolonged ?risk of FHF

CHRONIC HEPATITIS
 Persisting abnormality >6/12: histological, biochemical or clinical features of
hepatitis persisting beyond 6/12 (most usually blood tests abnormal >6/12).
 Ongoing hepatocellular damage of hepatitic type with inflammation and
necrosis accompanied by fibrosis.
 Progressive fibrosis may advance to cirrhosis.
 Fibrosis traditionally viewed as fixed/irreversible – current view is of fibrosis
as a more dynamic process with research interest in strategies to stop or
reverse fibrosis
 Syndrome with many causes

Presentations of chronic hepatitis

 Sometimes picked up in follow-up of acute hepatitis (e.g. HBV)
 Sometimes inherently chronic disease (e.g. auto-immune hepatitis) picked up
on investigation of symptoms/signs. Symptoms may be:
o Vague/generalised
o Occasionally mimic acute hepatitis +/- jaundice
 Sometimes picked up on routine testing (blood donation, health check) of
either the general population, pregnant women or those known to be high risk
 Sometimes identified only when progression to cirrhosis, including
complications/decompensation or signs of chronic liver disease

Similar biochemical abnormalities to acute hepatitis, although transaminases not

usually as elevated as in acute hepatitis. Albumin may be low with advanced
disease/cirrhosis

Old classification of chronic hepatitis

Looked at distribution and degree of ongoing hepatitic inflammation/damage to
try and indicate likely prognosis
 Chronic persistent hepatitis
o Inflammation confined to portal tracts, said to imply benign behaviour
 Chronic active hepatitis
o Inflammation in portal tract extending to involve adjacent parenchyma
(blurring sharp interface) with associated ‘piecemeal necrosis’, said to
imply more aggressive behaviour/risk of progression to cirrhosis.
The more extensive the CAH, the worse the outcome.

Criticisms of old classification

 Doesn’t indicate aetiology of chronic hepatitis (therefore, no guide for
treatment)
 Prognosis dependent additionally on aetiology (e.g. HCV) rather than simply
division into CPH or CAH (chronic HCV often has a CPH-like histology but still
has a high long-term risk of progression)
 Artificial distinction – two entities CPH/CAH are part of a spectrum in reality

New classification of chronic hepatitis

Indicates aetiology firstly (if necessary, qualify as “chronic” those diseases that
can also have acute forms). Then, pathologists assess chronic hepatitis for the
purposes of both prognosis and treatment decisions with a scoring system
considering “grade” and “stage” of disease separately (note: borrowing these
terms and changing their meaning somewhat from cancer pathology)

“Grade” is a score of disease activity (i.e. degree of inflammation & necrosis) to

indicate degree of ongoing damage.
o Within portal tract and at its edge (=interface/piecemeal)
o Within lobule of hepatic parenchyma
o Each of these elements is separately assessed and scored

“Stage” is a score of disease progression, with fibrosis/cirrhosis identified as the

key variable (degree of fibrosis up to cirrhosis assessed and scored)

Different scoring systems exist (e.g. Knodell, Metavir) but all use the same basic
principles. Problems in using scoring systems clinically arise because of
variations between pathologists or within the same pathologist at different times
of observation in applying the scoring system (inter- and intra-observer variation).

Causes of chronic hepatitis

 Chronic viral hepatitis (B, C, B+D or unknown)
 Auto-immune hepatitis
 Chronic drug hepatitis (but rare as drug usually withdrawn if recognised)
 Wilson’s disease (rare)
 Alpha-1-antitrypsin deficiency (rare)

Other causes of chronic liver disease are distinctive & considered separately –
but all chronic liver disease carries the risk of progression to fibrosis & cirrhosis:

 (Primary biliary cirrhosis & Primary sclerosing cholangitis)

These two are primarily chronic destructive diseases of bile ducts, leading to
chronic biliary obstruction/cholestasis, which is toxic and secondarily
damaging to liver cells. They are usually considered separately as they are
more “obstructive” in presentation than chronic hepatitis.

 (Steatohepatitis due to alcohol and mimics of alcohol-related liver disease)

Chronic alcohol abuse can cause chronic liver damage but with distinctive
features from causes of chronic hepatitis. Alcoholic steatohepatitis can be
mimiced by non-alcoholic steatohepatitis a/w metabolic syndrome. Both
considered separately

 (Haemochromatosis)
Iron overload in haemochromatosis causes liver cell damage and fibrosis, but
without significant inflammation. Considered separately
VIRAL HEPATITIS
Hepatotropic viruses
Hepatitis A & E (= “infective hepatitis”)
 Faecal/oral spread with enteral transmission
 No chronic state
Hepatitis B, C and D (= “serum hepatitis”)
 Parenteral transmission (body fluids, esp. blood)
 Chronic state possible (usual in HBV acquired early in life or in HCV)
 Other rare causes of “serum hepatitis” by as yet unidentified hepatotropic
virus
Yellow fever virus
 Restricted to equatorial Africa/America, often fatal acute hepatitis
 Monkey-mosquito-man transmission
Other viruses: EBV, CMV, rubella – cause hepatitis but clinical disease unusual
(transaminases/bilirubin may be abnormal though, other symptoms predominate)
  Viral infections can be combined (either co-infections or super-infections).
 Remember coinfection with HIV also alters clinical course of HBV/HCV

NOTE: EXTENSIVE OVERLAP WITH MICROBIOLOGY TEACHING

Hepatitis A
 Spread is faecal/oral with enteral transmission
 Direct personal contact with infected person
 Epidemic in institutional settings (e.g. crèche)
 Contaminated water or food (e.g. shellfish)
 Commonest preventable illness in travellers (travel to endemic areas)
 Usually subclinical/silent or mild illness but:
 10% get jaundice (relatively more in adults), sometimes profound and
persistent (cholestatic variant of hepatitis A)
 <0.5% FHF (increased risk if co-existing chronic liver disease)
 No chronic disease/chronic carrier state

HAV serology
anti-HAV develops during acute infection and gives lifelong immunity. Presence
of anti-HAV by itself largely meaningless as significant proportion of population
have been exposed to HAV (usually as silent/mild childhood illness or by
immunisation)

IgM anti-HAV specifically indicates acute infection (IgM response is present

during acute response only, before sustained IgG response develops)

IgM response in any viral or other serology test indicates an acute response, that
is recent infection – whereas IgG fraction merely demonstrates previous infection
Control:
 Active immunisation (if considered at risk, e.g. travel to high risk areas or
existing chronic liver disease) to induce protective anti-HAV antibody
 Passive prophylaxis with immune globulin if close exposure to known case

Hepatitis E
 Faecal/oral transmission and clinically similar to hepatitis A
 Mainly described in developing countries (India originally)
 Serological test not widely available
 Mostly subclinical/mild illness
 More serious acute disease (fulminant hepatic failure) rare, but more frequent
in pregnant women for some reason
 No chronic disease/carrier state

HEPATITIS B
Virus identified in 1966
300m worldwide chronic HBV disease
Leading cause chronic hepatitis, cirrhosis, liver cancer worldwide: 1m deaths
annually. Chinese men with chronic HBV: lifetime risk of “liver death” up to 40%

Prevalence differs widely depending on geography/risk group

 >8% prevalence carriage parts of SE Asia, China, W Pacific, sub-Saharan
Africa (in these areas, up to half of population exposed during lifetime)
 2-8% Mediterranean basin, Central and South America
 <2% N Europe, US, Australia, NZ (Ireland 0.1%, Irish prisoners 8%)

Virology
 Virus is 42nm sphere (= Dane particle): composed of two elements, surface
coat and core
 Complete virus only is infective
 Hepatitis B surface antigen (HBsAg) is present in surface coat
 Core contains hepatitis B core antigen (HbcAg), e antigen (HbeAg) and
HBV DNA
o Excess of surface coat material usually produced in HBV infection and
found as separate small subviral particles in blood in addition to
complete virus
 Sometimes, only surface coat particles present in blood. These are not
infectious in absence of (complete) viral particles.
 Complete virus particle (including DNA in core) must be present in blood for it
to be infectious

Distinguish terms: “infected” (refers to self) versus “infective” or “infectious” (that

is, potential risk to others who are exposed)

Hepatitis B virus is not directly cytopathic. It is the body’s immune response to

the HBV-infected hepatocytes that causes hepatocyte injury (as evidenced
by necrosis and inflammation on histology and elevated transaminases and
bilirubin on blood tests).
However, it is the immune response that also helps to control, clear and
eliminate HBV infection. Furthermore, some treatment of chronic HBV (e.g.
interferon alpha) is designed to stimulate/augment this immune response to
assist in the control and clearance of HBV, albeit at the cost of increased short
term damage.

Serology: Antigens (indicate presence of viral elements in blood, antigens

integral component of virus or virus-related particles)
 HBsAg indicates infection by HBV (but not necessarily presence of active
viral replication with complete virus in blood)
 HBcAg is not identified separately in blood by serological tests although it
does paradoxically stimulate an antibody response
 HBeAg is the antigen from the viral core that is usually identified in blood
during active viral replication (when there’s production of complete virus, i.e.
surface + core)
 HBeAg in blood therefore usually correlates with presence of HBV DNA in
blood and indicates infectivity because the complete viral particles required
for infection of others are present in the blood
 Caution: don’t rely 100% on presence of HBeAg to indicate infectivity/active
viral replication because of precore/core mutant viruses which are e antigen
negative (see Mutants)

Molecular virology: direct testing for HBV DNA most reliable for indicating
infectivity/active viral replication. Very sensitive but depending on method, may
be “over sensitive”, identifying tiny amounts of HBV DNA in blood that are
clinically irrelelvant and don’t represent infectivity or significant viral replication.

Serology: Antibodies (that is, elements of humoral immune response by body

to viral antigens, the body’s response)
 Antibody to HBsAg (anti-HBs) develops when infection is eliminated and is
the protective antibody against HBV infection
 Active immunisation by vaccination aims to produce anti-HBs
 Antibody to HBcAg (anti-HBc) indicates exposure only, not protective
immunity
 Anti-HBc can’t distinguish recovered from chronic disease
 IgM fraction of anti-HBc indicates recent acute infection/exposure (first
antibody response to develop) if it is necessary to establish this.
 Anti-HBe appears once HBeAg cleared (that is, generally indicating that
active viral replication has stopped), implying low risk of infectivity if still
HBsAg+. Clearance of HBeAg followed by appearance of anti-HBe is termed
HBeAg seroconversion and is the principal aim of treatment in chronic HBV.

HBsAg HBeAg IgM IgG anti- anti- HBV ALT

anti- anti- HBs HBe DNA
HBc HBc
Acute + +/- + +/- - +/- +/- High
infection

Chronic + - - + - + Low Normal

infection +
(low
replication
= carrier)
Chronic + + - + - - High Variable,
hepatitis + may be
(high elevated
replication)
Chronic + - - + - + High Variable,
hepatitis + may be
(high elevated
replication,
precore
mutant)
Vaccinated - - - - + - None Normal

Resolved - - - + + + None Normal

infection

Pathogenesis of HBV infection

The two determining factors for the various patterns of HBV infection are the
level of viral replication and the activity and effectiveness of the host immune
response. Age at infection is inversely related to the risk of developing
chronic infection. This is because two different patterns of response to HBV
infection can be distinguished which are age-dependent:

1. Active viral replication but immune tolerant: This pattern is typical of the
immature immune system of infected neonates/young children. For poorly
understood reasons, there is little immune response to the presence of
replicating virus for many years. High viral DNA in blood, lots of virus in liver
cells, but little inflammation and necrosis = high risk of chronic infection.

2. Active viral replication with immune response: Active immune response to

infection aims to clear HBV and is accompanied by necrosis and inflammation in
the liver and altered liver biochemistry. This pattern is typical of the newly-
infected adult and also develops in those with chronic infection since
infancy/childhood by the second/third decade of life as the immune system
matures and becomes responsive to HBV. Possible outcomes:

 Elimination of infection in newly-infected adults (outcome in >90%)

 Ongoing chronic infection with failure to eliminate virus and
development of chronic HBV infection (in <10% newly-infected adults)
 Persistence of chronic HBV infection (in those infected since
infancy/childhood), both the latter with the risk of fibrosis/cirrhosis/HCC
 3. Patterns of chronic HBV infection: active viral replication with
immune response = chronic hepatitis B
Chronic HBV infection (>6/12) with ongoing necro-inflammatory liver
damage associated with active viral replication with HBsAg, HBeAg
and HBV DNA in blood, although occasional mutant cases may be
HBeAg negative.
Immune response which causes damage also continues to try to
clear virus, some of these efforts being successful and some being
abortive.
Interferon treatment augments/stimulates these efforts. Such efforts
may be marked by clinical flares or exacerbations mimicking acute
hepatitis (rapid rise transaminases, increased liver damage, may be
clinically symptomatic).
As a result of these attempts at clearance, a % of patients with
chronic hepatitis clear the virus from the blood each year (i.e.
succeed in stopping active viral replication), usually accompanied by
seroconversion from HBeAg positive to anti-HBe positive. In some,
the immune clearance response may even convert the patient from
HbsAg positive to anti-HBs positive. However, the liver may already
be damaged by this stage in the course of chronic HBV infection.
This year on year % clearance of active replicating virus in chronic
infection is much lower in those chronically infected since
infacy/childhood than in those chronically infected at a later age.

4. Pattern of chronic HBV infection: successful immune clearance

response with conversion to inactive (non/low replicating) HBsAg+ carrier
state
Chronic HBV infection without evidence of ongoing necro-
inflammatory liver damage. Immune response succeeds in clearing
actively replicating virus from the blood. HBsAg positive but HBeAg
negative, anti-HBe positive and negative for significant amounts of
HBV DNA in blood. Insignificant risk of infecting others in this state.
Active immune surveillance maintains this state, so % risk every year
that some of these inactive chronic HBV carriers will revert to having
active disease (chronic HBV hepatitis). Increased risk of this
reversion associated with immunosuppression.

Patterns of transmission and disease in HBV infection

Transmission is parenteral (blood or body fluids)
Transmission does not occur via respiratory secretions, insect bite or casual
contact

High prevalence areas

 Vertical transmission by perinatal contact (mother to child)
 No trans-placental infection
 Neonatal infection very usually subclinical
 Immune tolerance up to 20s means that chronic HBV infection occurs in
>90% of those infected in neonatal period/childhood
 Large reservoir of infection in e.g. young women of child-bearing age because
of high rates of viral replication unchecked by immune response (tolerance)
 Immune response ultimately develops, but relatively low year-on-year rate of
viral clearance or stopping replication or HBeAg seroconversion compared to
immune response in those who acquire hepatitis B as adults.
 High risk of significant chronic liver disease, cirrhosis and HCC associated
with development of immune response.

Low prevalence areas

 Horizontal transmission (from one adult to another)
o Blood and blood products (now screened for blood-borne viral
pathogens)
o Intravenous drug users
o Haemodialysis units
o Health care (from patients to HCWs and [rarely] vice versa)
o Sexual contact (especially gay men and those with multiple partners)
o Tattoos, piercings, acupuncture
 Adult infection usually subclinical (75%), <0.5% fulminant hepatic failure
 No phase of immune tolerance following adult infection
 Immune response leads to clearance of HBV in 90% of cases adult acute
HBV
 Chronic infection develops in <10% of those infected in adulthood
 Some of those with chronic infection develop chronic hepatitis B,
whereas others become inactive chronic carriers.
 Dynamic interplay between chronic HBV infection and immune response, so
active movement between these two clinical states (see above: pathogenesis)
 Those with chronic hepatitis B are at risk of ongoing chronic liver damage,
cirrhosis and HCC, whilst also being infectious (or infective) to others.
Associated with significant HBV DNA in blood and usually HBeAg positive.
 Inactive chronic carrier state generally considered to remove risk of chronic
damage and risk of infecting others. Associated with insignificant HBV DNA in
blood and always HBeAg negative.

Intermediate prevalence areas

Intermediate between two patterns. Infection in childhood after neonatal period
thought to be important in Africa, from child to child contact (via cuts or infected
toys or personal objects). Infection in childhood likely to lead to chronic disease.

Approaches to treatment and control

Vaccination: confers protection in high %, check for response to vaccination
 Universal at birth in high prevalence areas (to interrupt vertical transmission)
 At-risk groups in lower prevalence areas (HCWs, IDUs, gay men, children of
HB+ mothers)
 Passive protection with pooled Ig (pooled from HB-immune donors, i.e. anti-
HBs positive) following at-risk exposure (esp if not previously vaccinated)

Treatment: check current therapeutics

 Interferon-alpha - boosts active immune response, may cause transient
disease flare/exacerbation, difficult side effects (haematological, fatigue,
psychiatric) and awkward to administer
 Nucleoside analogues e.g. lamivudine inhibits viral replication
 Problems in high prevalence areas – cost/logistics of vaccination and drugs

HBV positive health care workers – ethical/industrial relations issues.

Avoid exposure prone procedures.

Mutant viruses
 Pre-core/core mutants: e antigen negative despite active viral replication. Can
cause HBeAg negative chronic hepatitis B, must then rely on looking for HBV
DNA
 Mutant s antigen, may make unresponsive to vaccination or allow escape
from vaccination protection in those who were previously protected

Hepatitis D virus (=Delta agent)

 “Passenger” RNA virus - requires presence of HBV for replication
 Either co-infection (same time as HBV) or super-infection (after original HBV
infection) with hepatitis B possible, latter worse
 Increases risk of chronic disease (HBV+HDV worse than HBV alone),
commonest in IDUs, varying geographical incidence

Remember that other co-infections or super-infections with viruses damaging the

liver or affecting the immune system can occur (e.g. HBV+HCV, either or both
with HIV or HAV superinfecting HBV or HCV)

HEPATITIS C
 Non-A non-B hepatitis defined after recognition of HBV. Caused hepatitis
related to blood/blood products not due to HBV (after ?10% of transfusions)
 HCV identified 1989 as major cause of non-A, non-B hepatitis
 Although aetiology of % of acute (and presumed viral) hepatitis still
unidentified (are there other yet-to-be-characterised hepatitis viruses?),
transfusion-related hepatitis now extraordinarily rare
 Prevalence of HCV <2% in developed countries (0.2% UK blood donors, 37%
of Irish prisoners)
 Worlwide, higher prevalence elsewhere, ?300million with active infection
worldwide
 6 distinct genotypes (with subtypes) – important for treatment response and
epidemiology, 1 and 2 predominant types in Ireland (genotypes 2 & 3 respond
to interferon alpha treatment better than genotype 1)

Transmission of HCV
 Blood & blood products (now <1/100,000 risk in blood screened for HCV) – in
past, pooled blood prodcuts major route of transmission, e.g. haemophiliacs,
Irish women given contaminated anti-D globulin
 Intravenous drug users
 Perinatal? Sexual? Household? Do not seem to be common means of
transmission
 % of “sporadic” cases. Precise means of transmission unclear

Pattern of disease
 Acute infection almost always mild/subclinical
 Chronic infection develops in 80%
 ?Lower rates in those infected in childhood, Irish anti-D cohort
 Chronic infection persists, low rate of spontaneous clearance
 Chronic infection leads to significant damage (fibrosis, cirrhosis, HCC) over a
long time course, can take over 30 years
 20% develop cirrhosis over 20 years is a typical average estimate
 Risk of progression greater in: men, age>50, use of alcohol, co-infection
(HIV), type 1 HCV genotype, those with more active liver necrosis and
inflammation

Patient with chronic HCV

 Vague symptoms (malaise, fatigue, joint pains) - ?specifically due to chronic
HCV, don’t necessarily correlate with histological or biochemical changes
 Often incidental pick-up (except if known history of risk)
 Histology may be abnormal despite normal enzymes (from experience with
anti-D women); histological activity best predictor of risk of progression and
need for treatment

Pathogenesis: uncertain – virus directly cytopathic or immune response to virus?

HCV Serology
 anti-HCV antibody not protective, indicates exposure only, and because of
high frequency of chronic infection usually taken to mean ongoing infection
until confirmed by virology
 anti-HCV: 3rd. generation ELISA is usual screening test BUT problems with:
o false negatives, in early infection (before antibody made), if suspicious
 test for HCV RNA
o false positive, relatively common with ELISA, use anti-HCV RIBA test
to confirm. RIBA more specific but technically more difficult than ELISA
 No protective antibody, therefore no current prospect of developing vaccine

HCV Molecular virology

 Most accurate means of identifying ongoing HCV infection
 Presence of HCV RNA in blood definitively indicates ongoing infection
 Quantitation may indicate viral load (risk of progression)
 Virus may be genotyped (stratifying risk of progression, likelihood of response
to treatment)

Treatment: check current therapeutics

 Interferon-alpha: high response rate, high relapse rate
 Generally use if active hepatitis +/- fibrosis, genotype 2/3, ?slows
progression/reduces risk of liver cancer (check current indications in
therapeutics)
 Ribavirin: specific anti-viral
 Liver biopsy (not enzymes) & genotype determines treatment: best indicator
of degree of damage and therefore appropriateness of therapy

Extra-hepatic effects of HBV and HCV

 10% of chronic HBV may get extra-hepatic manifestations related to immune
complex deposition: polyarteritis nodosa (PAN), membranous
glomerulonephritis

 Extrahepatic manifestations common in chronic HCV (immune complex

disease causing cryoglobulinaemia, autoimmune disease including thyroid
disease, skin manifestations such as porphyria cutanea tarda)

 Auto-antibody levels (RF, ANF, SMA) may be elevated in chronic HCV, may
make diagnosis of HCV/distinction from e.g. autoimmune hepatitis difficult

Needle stick injury: check current management

Parenteral exposure of HCWs to potential risk of blood borne viral infection

HCWs should be immunised against HBV

Risk from single injury with positive blood if non-immune: 8-30% HBV, 2-3%
HCV, 0.3%HIV

Problem with HCV: high rate of progression, no prevention possible

Irish Blood Transfusion Service

Blood and blood products are tested for:
HBV (HBsAg and anti-HBc, the latter indicating exposure)
HCV
 HIV
HTLV
Syphilis

CMV is also tested for in order to identify a specific pool of CMV-negative blood.

Other countries may test for additional surrogate markers (e.g. ALT in US).

Risk of transfusion-related hepatitis dropped dramatically even before

identification of HCV (testing for HBV, then HIV, donors’ risk factors assessed)

Routine serology in ‘viral hepatitis screen’ – what do you get?

 IgM anti-HAV (is there acute HAV?)

 HBsAg (is there HBV infection, acute or chronic?)
 Anti-HCV, screening ELISA followed by confirmatory RIBA if ELISA
positive (is there exposure to HCV, therefore likely ongoing infection?)

 If HBsAg is positive, check for HBeAg and anti-HBe to look for

infectivity/active viral replication
 If HBeAg is negative but liver enzymes are elevated, the person may have
HBeAg-negative chronic hepatitis B (pre-core/core mutant), check for HBV
DNA
 If anti-HCV is positive, do molecular virology to confirm presence of HCV
RNA, estimate viral load and genotype virus
 If you want to establish if someone is HBV immune, test for anti-HBs
 If you want to establish if someone has ever been exposed to HBV, test
for anti-HBc

Non-viral liver infections

Parasites typically geographically restricted but note current patterns of travel,

tourism and migration
 Amoebic cysts, hydatid (Echinococcus) cysts
 Schistosomiasis (ova in portal tracts causes portal fibrosis and non-cirrhotic
portal hypertension)
 Liver flukes (bile duct obstruction, risk of bile duct adenocarcinoma)

Bacteria

 Ascending cholangitis (occurs secondary to obstructed biliary tract, serious

acute illness – see lecture five)
 Infection ascending via portal venous system from intra-abdominal sepsis
(e.g. in pre-surgical/sterile era a/w appendicitis or neonatal umbilical sepsis or
 now ulcerated bowel cancers or inflamed diverticular disease)

o Liver (hepatic) abscess may arise in each of the above situations

Lecture 3 - Key Revision

 Understand acute and chronic hepatitis
 What are the causes of acute hepatitis?
 What causes chronic hepatitis and what are its consequences?
 How is chronic hepatitis assessed?
 Distinguish hepatitis A, B & C: transmission, risk of chronicity
 Understand pathogenesis of HBV infection (adults vs. neonates)
 Understand the worldwide burden of chronic HBV and chronic HCV infection
 Understand HBV serology: the significance of HBsAg and HBeAg, anti-HBs
 Understand HCV serology & virology and risk of disease progression

• Lecture series on diseases of liver and biliary tract prepared April 2011 by:
• John O’Dowd, Department of Pathology, Royal College of Surgeons in Ireland,
Education and Research Centre Beaumont Hospital
• Any suggestions, comments or corrections on these notes welcome on email
• email address <[email protected]>

LIVER, PANCREAS & BILIARY TRACT

Lecture No. 4
John O’Dowd

Outline of Lecture
 Spectrum of fatty liver disease: fatty change & steatohepatitis
 Alcohol-related liver disease
 Non-alcoholic fatty liver disease (NAFLD)
 Haemochromatosis
 Spectrum of autoimmune liver disease
o Autoimmune hepatitis
o Primary biliary cirrhosis
o Primary sclerosing cholangitis
 Cirrhosis: classification & causes

Lecture No. 4 - Learning Objectives

 Understand the spectrum of fatty liver disease (fatty change,
steatohepatitis, cirrhosis)
  Understand what is meant by fatty change, what is its significance & what
causes it
 Know how alcohol affects the liver
 Understand the spectrum of pathological effects of alcohol
 Understand what is meant by non-alcoholic fatty liver disease & what is its
significance
 What is hereditary haemochromatosis? How is it diagnosed and treated?
 What are the similarities & differences between autoimmune hepatitis &
primary biliary cirrhosis?
 How is autoimmune liver disease diagnosed?
 What is cirrhosis? What are its causes? Revise its complications

FATTY LIVER DISEASE

Spectrum of changes:
 Fatty change of macrovesicular type (commonest by far)
 Steatohepatitis – from mild to more marked, which cases might progress?
 Cirrhosis

Causes:
 Alcohol: classic cause
 Rarer specific causes e.g. amiodarone, TPN, starvation, acquired
lipodystrophy a/w HAART
 Other common cause: non-alcoholic fatty liver disease (NAFLD) a/w type
2 diabetes, insulin resistance, obesity, hyperlipidaemia (i.e. a/w so-called
metabolic syndrome)

FATTY CHANGE

Two distinct types: macrovesicular and microvesicular, according to size and

number of fat droplets within hepatocytes

Macrovesicular fatty change much commoner = single, large droplet

Macrovesicular fatty change is a predictable short-term and reversible response
to altered hepatocyte metabolism, whether a/w significant alcohol intake or
metabolic syndrome. It is fatty change of the usual type and is implied when the
term “fatty change” is used without qualification.

Causes of macrovesicular fatty change (i.e. fatty change of the usual type)
 Alcohol
 a/w metabolic syndrome (insulin resistance syndrome)
 Starvation or sudden weight loss, TP, drugs (amiodarone, HAART)

Microvesicular fatty change is caused by a toxic accumulation of reactive fatty

acids as multiple droplets within individual hepatocyte mitochondria. Typically
associated with fulminant hepatic failure. All causes of microvesicular fatty
change very rare.

Causes of microvesicular fatty change

o Acute fatty liver of pregnancy
o Reye’s syndrome
o Tetracycline toxicity

STEATOHEPATITIS

 Hepatitis in association with fatty change & sharing the same aetiologies
 Distincitve histology:
 Characteristic pattern of inflammation and necrosis, including neutrophils,
lobular distribution centred on vicinity of hepatic vein branch (i.e. zone 3)
 “Ballooning” degeneration of liver cells as well as background fatty change
 ‘Mallory’s hyaline’ present within liver cells
o Pink intracytoplasmic inclusions which indicate liver cell injury, formed
from intracellular aggregates of damaged cytokeratin proteins
o Typical for steatohepatitis but not specific
 Perivenular fibrosis, that is fibrosis centred around small central hepatic
vein branches (zone 3) – in contrast to fibrosis in conventional chronic
hepatitis which is portal/periportal (centred on zone 1)

ALCOHOL & THE LIVER

 Broad correlation between duration/amount of alcohol consumed and risk of
alcoholic liver disease
 However only 30% of chronic alcohol abusers develop alcoholic hepatitis,
only 10-15% develop cirrhosis
o Host factors important clearly
o Predisposing risk factors: female>male, ?genetic factors, ?nutritional
factors, co-existing liver disease in some patients
o Pattern of drinking (e.g. binge), drinking spirits vs. wine: no evidence

 “Safe limits”: men 21 units/week, women 14 units/week: from UK

RCP/RCGP/RCPsych – controversial, both concept and quantities
o Within “safe limits”, relatively higher intakes may still be associated
with small overall increase in mortality
o 1 unit = 10g alcohol = ½ pint beer, small glass wine
o Intake >80g (8 units)/day = 50% risk of alcoholic liver disease
 Relationship of alcohol to all-cause mortality

 J-shaped’ curve linking alcohol consumption to all-cause mortality, i.e. all-

cause mortality slightly lower at low/moderate alcohol intake compared to nil
alcohol intake (abstainers) or higher alcohol intakes.
 Positive benefits of low intake? On IHD, ischaemic stroke, CRF, DM?
 Most marked benefit in older men (in whom IHD common cause of death)
 Criticisms:
o Studies compare abstainers to those with low/moderate intake
o Abstainers not a uniform group: includes sick people, ex-alcoholics
 Remember alcohol doesn’t just affect mortality – significant cause of
morbidity and social harm
o May be risky patterns of drinking rather than average intake that is
sometimes more significant (e.g. binge versus regular, low intake)

• Alcohol metabolism – in liver through:

 Oxidative pathway via alcohol dehydrogenase to acetaldehyde, then via

acetaldehyde dehydrogenase to acetate, main pathway normally
 Microsomal ethanol oxidising system pathway (MEOS) which is minor
normally but induced in heavy drinkers, produces reactive intermediates

Pathogenesis of liver injury related to alcohol

 Acetaldehyde toxic
 Production of free radicals via MEOS pathway
 Acetaldehyde- or free radical-modified proteins antigenic?
o Potential to stimulate immune response, inflammation

Patterns of Alcohol-Related Liver Injury

 Fatty change = macrovesicular steatosis
o Dose dependent accumulation of triglyceride in hepatocytes,
reversible, common.
o Short term consequence of significant alcohol intake on liver cell fat
metabolism.
o By itself innocuous. Only significance is that if excessive drinking
continues, person may be at risk of alcoholic liver disease

 Alcoholic hepatitis
o Classic “acute” presentation rare
o Varies in degree from mild to severe (latter with risk of mortality)
o One third at least go on to cirrhosis if drinking continues
o Abstinence averts this risk
o Synonymous with alcoholic steatohepatitis (i.e. alcoholic hepatitis
associated with fatty change)

 Cirrhosis +/- complications

Presentation of significant alcohol-related liver damage may be:

 Asymptomatic or with vague symptoms (may be suggested by blood tests)

 Classic alcoholic hepatitis – malaise, jaundice, low fever, tender
hepatomegaly, raised WCC (neutrophils), elevated transaminases, typically
<500 and AST:ALT >2.0 + features of decompensated liver disease in
absence of cirrhosis (HE, HRS type 2, ascites) – mostly, no clear trigger.
Significant risk of mortality.
 Cirrhosis +/- decompensation

 Don’t assume because there is alcohol abuse that it is the sole or even main
cause of the liver disease present – consider interactions with HCV,
haemochromatosis, sensitisation to paracetamol toxicity

Diagnosis – based on history (but alcohol use may be denied/minimised,

collateral useful, “CAGE” questionnaire useful screening tool)

 “Hints” of alcohol abuse – that is, sometimes suggestive if alcohol history

denied:
o Raised GGT, elevated MCV, elevated AST & ALT with AST:ALT>2.0
o But none especially sensitive or specific so caution

PATHOLOGICAL EFFECTS OF ALCOHOL ABUSE

 Alcoholic liver disease (hepatitis and cirrhosis, complications of cirrhosis)
 Acute and chronic pancreatitis (chronic pancreatitis rare in a/w cirrhosis due
to alcohol for some reason)
 Gastritis, erosions & peptic ulcers, oesophageal tears
 CNS disturbance (thiamine deficiency leading to acute Korsakoff psychosis or
Wernicke’s encephalopathy, cerebellar atrophy, cortical atrophy, global
cognitive impairment)
 Acute myopathy, muscle wasting and peripheral neuropathy
 Dilated cardiomyopathy (alcohol commonest cause apart from ischaemia)
 Possible malnutrition and increased risk of infection (e.g. lobar pneumonia &
TB in malnourished alcoholics)
 Risk of trauma (head injury, fractures, RTAs, suicide)
 Foetal alcohol syndrome in offspring of mothers with heavy alcohol intake
(risk of adverse effects in mothers with low intake probably insignificant)
 Alcohol increases risk of hypertensive stroke, oral, oesophageal and breast
cancer

NON-ALCOHOLIC FATTY LIVER DISEASE

 First identified in countries where abstinence from alcohol is the rule.
 Now increasingly diagnosed in e.g. North America/Europe
 Spectrum of histological changes identical to alcohol-induced liver
disease, that is:
o Fatty change (most common manifestation by far)
o Non-alcoholic steatohepatitis (NASH), much less common, but as with
alcoholic steatohepatitis, risk of progression to -
o Cirrhosis
o However, risk of progression from NASH to cirrhosis much lower than
with alcoholic hepatitis

Typical clinical association of NAFLD (but not always) is with metabolic

syndrome (=syndrome X/insulin-resistance syndrome) (i.e. patients prone to
obesity, type 2 diabetes and hyperlipidaemia + abstinent/low alcohol intake)

 Increased recognition of NAFLD, identified now as relatively common

(possibly = HCV in prevalence)
o ?Commonest reason for abnormal liver blood tests (elevated
transaminsases) referred to liver clinics if other specific causes
excluded
o ?Commonest reason for otherwise unexplained or cryptogenic
cirrhosis

 Questions:
o How can we identify which patients with abnormal liver blood tests may
have NASH?
o What is the rate or risk factors for progression in any given individual if
they have NASH? Why do those few who progess do so?

 Recommendation: lose weight, control lipids/diabetes, then review LFTs.

 Lipid lowering with statins improves abnormal LFTs in presumed NAFLD

HAEMOCHROMATOSIS
Excessive deposition of iron in tissues causing damage

 Hereditary haemochromatosis (=HFE)

o Specific genetic defect, progressive excessive absorption of iron
 relative to need
 Secondary haemochromatosis (=haemosiderosis)
o External source of excess iron
o Multiple transfusions (e.g. haemoglobinopathies such as thalassaemia)
o Associated with alcohol abuse, other forms of chronic liver disease
(e.g. chronic HCV, NASH)
o Clinical disease unusual with secondary haemochromatosis

Iron deposition toxic, specifically affects the following tissues:

 Liver stimulating fibrosis and ultimately cirrhosis (doesn’t cause inflammation)

 Endocrine pancreas (rare cause of adult onset DM)
 Myocardium (rare cause of congestive heart failure/dilated cardiomyopathy)
 Anterior pituitary (secondarily causes hypogonadism and impotence in men)
 Joints (HFE a/w arthropathy with pseudo-gout due to calcium pyrophosphate
crystal deposition disease in knee)
 Fatigue (common symptom), skin hyperpigmentation (bronze diabetes)

Normal iron metabolism

 Absorption in duodenum and jejunum into enterocytes and then released into
blood in controlled amount proportional to need (losses precisely
compensated by absorption)
 Limited ability to lose iron – e.g. via shed skin or GI surface cells, in women
via menstruation, lactation and loss at delivery – reason why women more
likely to be in negative iron balance but protected from clinical manifestations
of haemochromatosis
 Transported in blood bound to transferrin
o Normally <30% of the total transferrin iron binding capacity saturated

 Stored in liver, spleen, marrow

o Storage forms ferritin (short term), haemosiderin (longer term)
 Ferritin can be measured in blood, level reflects iron stores
o Ferritin also an acute-phase reactant (i.e. inflammatory) protein, so
caution as raised level not specific for excess iron stores, as also
raised in any cause of significant acute or chronic inflammation
o Very high levels strongly suggestive of HFE though
o Good for following up response to treatment (venepuncture)

 Normal total body iron load 3-4g, mostly in haemoglobin and other haem-
containing enzymes, about 1g in stores

 Hereditary haemochromatosis progressive excess absorption of iron through

SI, difficult to compensate for by loss except in menstruating/pregnant women
 Clinical symptoms rare before 40 in men, later if at all in women
 Clinical symptoms 4x commoner in men than women
Hepcidin: blocks release of absorbed iron from enterocytes into blood and from
stored iron in ferritin into blood. Now recognised as a key protein – all forms of
HFE associated with low levels or decreased function of hepcidin, leading to
increased absorption and increased blood levels of iron.

Evidence of biochemical iron overload

 Ideally fasting sample
 Serum iron unreliable on its own
 Ratio of serum iron to transferrin (transferrin = total iron binding capacity)
most informative, usually expressed as %saturation of TIBC.
 Values over 55% satuaration usual cut off for evidence of iron overload
 High ferritin (>200 in women, >300 in men) suggests iron overload, but less
sensitive and less specific for diagnosis (see above) but good for monitoring
treatment response

Hereditary haemochromatosis (HFE)

 Autosomal recessive

 HFE gene on chromosome 6p – two common mutations C282Y and H63D

o 85% of HFE patients homozygous for C282Y mutation (C282Y/C282Y)
o Compound heterozygotes (C282Y/H63D) have a 60% risk of
intermediate iron overload/mild clinical disease
o Heterozygotes (C282Y/wild type or H63D/wild type) do not seem to be
at increased risk of clinical disease
o If heterozygous and patient has chronic HCV, abuses alcohol or has
NAFLD, does genetic status increase severity/risk of chronic liver
disease?

 Traditional view: rare, inherited disorder

 Now: genetic disease identified in 4-5/1000 as iron storage studies or genetic
screening more frequent
 Disease has variable penetrance, therefore:
 Genetic disease commoner than evidence of biochemical iron overload
 Most identified with biochemical iron overload are asymptomatic or have non-
specific symptoms (joint pain or fatigue)
 Biochemical iron overload associated with significant tissue damage rarer

 HFE may not be thought of as contributing to or causing heart failure or

diabetes

Diagnosis of haemochromatosis

Blood tests for assessment of iron storage status

 %Saturation of Total Iron Binding Capacity (calculated as ratio of serum iron
to serum transferrin)
 Ferritin (but best for treatment follow-up rather than diagnosis

 Genetic testing if abnormal iron storage status confirmed

 Liver biopsy less common

o Amount/type of iron deposition assessed qualitatively
 Iron demonstrated as bright blue deposits by Perls’ stain for
haemosiderin
o Iron content of tissue can be measured quantitatively (now unusual)
o Stage - i.e. extent of any fibrosis

Treatment of haemochromatosis safe and easy: venepuncture

 Screen first-degree relatives (siblings, children) at 18-30yrs for disease

 Potential for population screening? But

o What % of individuals with genetic or even biochemical disease will
develop serious clinical manifestations? Unclear and controversial,
probably relatively few as disease has variable penetrance

 Do not want to identify a lot of people who will never develop significant
clinical disease anyway (even if treatment safe and relatively straightforward)

WILSON’S DISEASE

 Very rare cause of liver disease but potentially treatable

 Presentation typically <40 years
 Difficult to diagnose, can present resembling acute hepatitis or as hepatic
failure, chronic hepatitis or cirrhosis, mimicking other commoner causes of
acute and chronic liver disease
 Inherited, autosomal recessive disorder of copper metabolism/accumulation
 Failure by hepatocytes to transport copper by normal routes, toxic
accumulation in liver cells and elsewhere
 Diagnosis: low serum caeruloplasmin (Cu transport protein), high urinary
copper
 Caeruloplasmin is an acute phase reactant and will be elevated in a/w any
inflammatory condition, which may mask Wilson’s disease
 Multiple possible mutations in gene on chromosome 13 identified that may
cause Wilson’s (i.e. no single/common defect – top three mutations in UK
account for only one third of cases), therefore:
o Individual patients are often compound heterozygotes for 2 different
mutations (i.e. different defects inherited from each carrier parent)
o Although much more difficult to screen for than other inherited
diseases (e.g. HFE) because of multiplicity of possible mutations,
once mutation in index patient characterised, can then be used to
 screen first degree relatives

 Copper accumulation causes damage to: liver, brain (esp. basal ganglia),
haemolytic anaemia, eyes, kidney = hepato-lenticular degeneration
o Kayser-Fleischer rings in cornea
o May have neuro-psychiatric symptoms
o Treatment: chelating agent penicillamine to remove copper

ALPHA-1-ANTITRYPSIN DEFICIENCY

 Very rare cause of liver disease

 Typically presents in childhood but sometimes as an adult
 Liver disease with A1AT deficiency may mimic other commoner causes of
acute and chronic liver disease
 A1AT is the major extracellular protease inhibitor (Pi), produced by liver
 Gene on chromosome 14, lots of variations, inherited abnormalities
o ‘Normal’ phenotype PiMM (>80% of people), ‘Pi’ stands for
protease inhibitor
o ‘Z’ commonest abnormal type, not secreted by liver, therefore low
blood levels, toxic accumulation in liver
o With PiZZ phenotype, serum levels of A1AT <50% normal
o ‘Null’ abnormal type also occurs, zero blood levels, but no abnormal
type accumulates in liver

 A1AT deficiency may cause emphysema (due to unopposed protease [esp.

elastase] activity in lung tissue, this gives insight into pathogenesis of
commoner form of emphysema related to cigarette smoking)
 PiZM phenotype: normal A1AT levels but increased risk of emphysema with
smoking – is there increased susceptibility to liver damage from other
causes?
 Remember: smoking is far commoner cause of emphysema than A1AT def.
Spectrum of Auto-Immune Liver Disease
Characterised by auto-antibodies (markers of autoimmune damage, rather than
usually the cause of the autoimmune damage) and elevated immunoglobulin
levels

Occasional overlap/transformation between the three principal entities:

 Autoimmune hepatitis
o Resembles other types of chronic hepatitis clinically
o Predominantly elevated transaminases
o Type 1 (“classic”) positive antinuclear antibody (ANA), positive
smooth muscle antibody (SMA), negative antimitochondrial
antibody (AMA)
o Type 2 positive liver kidney microsomal antibody (anti-LKM)
 o Elevated IgG levels

 Primary biliary cirrhosis

o Chronic intrahepatic cholestasis
o Predominantly obstructive enzymes
o Positive AMA, negative ANA/SMA
o Elevated IgM levels

 Primary sclerosing cholangitis

o Chronic intrahepatic and/or extrahepatic cholestasis
o Predominantly obstructive enzymes
o If intrahepatic disease mainly (no extrahepatic disease on
MRCP/ERCP), differential diagnosis is with PBC but:
o Negative AMA, negative ANA/SMA
o Normal Ig levels
o Positive p-ANCA

Blood tests to screen for autoimmune liver disease

 Liver auto-antibodies (ANA, SMA, AMA, anti-LKM, sometimes p-ANCA)
 Immunoglobulin subtype levels

Note about auto-antibody names

The names of auto-antibodies typically refer to their pattern of reaction in specific

“test” tissues in the laboratory – e.g. ANCA, SMA, ANA, AMA, ALKM. The test
tissues are usually of animal origin. The names themselves don’t necessarily
imply anything about the clinical diseases with which they are associated. For
example, SMA is commonly positive in autoimmune hepatitis but has nothing to
do with muscle diseases or smooth muscle pathology in patients – the name
smooth muscle antibody merely describes its pattern of reaction in an animal test
tissue.

AUTO-IMMUNE HEPATITIS
 Syndrome of chronic autoimmune damage to hepatocytes with necrosis and
inflammation associated with elevated serum globulins, presence of auto-
antibodies and response to treatment with immunosuppression

 Clinical presentation heterogeneous, varies from insidious onset to acute

hepatitis-like illness (although illness always chronic from start, no true acute
version) to presentation with cirrhosis or its complications
 Jaundice at some time in 40%: this gives opportunity for diagnosis
 Course: relapsing/remitting or relatively direct progression to cirrhosis
 Resembles other forms of chronic hepatitis/chronic liver disease & therefore:
 Exclude other causes of liver disease.
 All features not present in every patient, diagnosis may be difficult, scoring
systems devised to assist making diagnosis of AIH

 Typical patient: Female>>male, 20-40 years

 Often associated with auto-immune disease elsewhere

 Importance of diagnosis: effective treatment with immunosuppression

(steroids, maintenance with azathioprine), may be tried as a trial of treatment
even if diagnosis uncertain, of use even if cirrhosis a/w AIH

 Classification based on types of auto-antibody present:

o Type 1 (‘classic’ AIH), anti-nuclear and anti-smooth muscle antibodies
positive (ANA+ and SMA+), typically in high titres
o Type 2 anti-LKM antibody (ALKM) positive, rarer than type 1, better
outcome
o Anti-mitochondrial antibody (AMA) negative (excludes PBC)
o Auto-antibodies just markers of disease, not involved in pathogenesis
o Pathogenesis actually involves T-cell mediated damage to hepatocytes
o
Chronic cholestatic diseases
Chronic bile retention (cholestasis) harmful to liver cells, induces chronic
inflammation with potential to develop significant fibrosis and cirrhosis

Primary autoimmune bile duct disease

 Primary biliary cirrhosis (PBC) – intrahepatic bile ducts
 Primary sclerosing cholangitis (PSC) – typically involves both intrahepatic and
extrahepatic bile ducts but involve one and not the other

Autoimmune inflammation & damage to bile ducts, causing chronic cholestasis

and ultimately leading to loss of intrahepatic bile ducts.

Secondary to other causes of chronic cholestasis

 If long-standing, such liver damage may go on to cirrhosis, but this is very

rare. When it occurs, it is termed secondary biliary cirrhosis
 Typical causes of extra-hepatic duct obstruction – such as stones or tumour -
very rarely cause this (because these conditions are either relieved or result
in death before the secondary liver damage happens, respectively)
 Strictures, childhood congenital biliary tract atresia or abnormalities (e.g.
choledochal cysts) and chronic extrahepatic biliary tract obstruction due to
cystic fibrosis can cause secondary liver damage with fibrosis and potential
cirrhosis (i.e. secondary biliary cirrhosis)
PRIMARY BILIARY CIRRHOSIS
 Syndrome of chronic auto-immune inflammatory damage/destruction of
intrahepatic bile ducts leading to chronic cholestasis & loss of bile ducts
 30% have granulomas associated with bile duct inflammatory damage
 Typical organ-specific auto-immune patient profile: F>M by 10X, 30-60, often
associated with other auto-immune diseases
 Clinical: asymptomatic (may be picked up on blood tests), pruritus, fatigue,
skin hyperpigmentation, osteoporosis, complications of cirrhosis
o Pruritus may be intractable, due to retained bile salts
o Jaundice a late feature, indicating advanced disease
 Very high alkaline phosphatase, high IgM, bilirubin, hypercholesterolaemia
o Consider drug-induced cholestasis in differential diagnosis
 Characteristic auto-antibody: anti-mitochondrial antibody positive in >90%
o If AMA positive, test for specific M2 subtype
 Treatment: not steroids (worsens bone disease), ursodeoxycholic acid
(UDCA, increases bile salt transport – improved outcome in those who show
a biochemical response to UDCA treatment), orthotopic liver transplant

 “Cirrhosis” in the disease name is misleading - only cirrhosis in late

(terminal) stage, prior to that various degrees of damage that are short of
cirrhosis, initially inflammaton of bile duct branches in portal tracts
o Symptomatic disease takes approx. 10 years to progress to cirrhosis
o Disease named “cirrhosis” in first place because originally only
identified at autopsy in its late stages
o Disease increasingly identified at asymptomatic stage by liver blood
tests, much slower progression than in historical case series

PRIMARY SCLEROSING CHOLANGITIS

 Chronic fibro-obliterative destruction of bile ducts, likely autoimmune aetiology
 Unlike PBC, both intrahepatic and extrahepatic ducts (most commonly) or
either may be affected
 If intra-hepatic mainly, progressive cholestasis with features similar to PBC,
going on to cirrhosis
 If extra-hepatic mainly, CBD strictures with obstruction, risk of cholangitis
 M>F by 4X, much less common disease than PBC
 May resemble PBC closely in presentation but auto-antibody profile different
o AMA negative, ANA/SMA may be positive, p-ANCA positive
o ERCP shows typical ‘beaded’ pattern in CBD related to extrahepatic
bile duct strictures if present
 Strong association with inflammatory bowel disease, especially UC
 IBD in 70% of patients with PSC - but PSC present in <<5% of UC patients
(UC much more common than PSC) – PSC may present before or after UC
 Increased risk of bile duct adenocarcinoma (cholangiocarcinoma) and of IBD-
associated colonic adenocarcinoma compared to IBD patients without PSC

CIRRHOSIS
 Diffuse replacement of normal liver architecture by bands of fibrosis
separating regenerative nodules of liver cells
 Traditionally viewed as largely irreversible (view now revised)
 Causes altered vascular relationships in liver
 Chronic end-stage state following continuing damage/loss of liver cells and
associated ongoing fibrosis
 May or may not have residual inflammation
 Prognosis worse if continuing inflammation
 Specific treatment for underlying disease may improve prognosis
(immunosuppression if autoimmune hepatitis, venesection if
haemochromatosis, abstinence if alcohol-related etc)
 50 years ago: always presented with complications/decompensaton, disease
state well established
 Now: presents more often at earlier stage (e.g. by screening blood tests)
 Recognition that fibrosis may be a dynamic state, research interest in
developing anti-fibrotic agents to prevent progression, possibly regression

Classification
 By cause – most meaningful but sometimes none identified (“cryptogenic”)
 Morphology - size of regenerative nodules
o Macronodular (>3mm in size)
o Micronodular
o Little relevance because cause of cirrhosis and consequences of
disturbed liver function most important, irrespective of morphology
CAUSES OF CIRRHOSIS
 Common
o Alcoholic
o Chronic viral disease (HBV, HCV)
o “Cryptogenic” (no cause found, ?but many/most related to NASH)
 Less common
o Haemochromatosis (treated by venesection)
o Auto-immune hepatitis (treated by immunosuppression)
o PBC & PSC
o Non-alcoholic steatohepatitis
 Rare
o Wilson’s disease (rare but treatable)
 o Alpha-1-antitrypsin deficiency
o Childhood causes including in-born errors of metabolism, congenital
biliary tract abnormalities causing chronic cholestasis and cystic
fibrosis

Prognosis

 Child-Pugh scoring system informative about prognosis of cirrhosis and risk of

surgery (includes ascites, bilirubin, albumin, PT and hepatic encephalopathy),
need to consider transplant
 Poor prognosis once cirrhosis develops complications (i.e. becomes
decompensated)

Diagnosis of cirrhosis: usually based on combination of suggestive features in

history, clinical presentation and blood tests and radiology (typically shrunken,
nodular liver).
Blood tests in a patient with stable (compensated) cirrhosis may only show minor
abnormality.
Diagnosis requiring liver biopsy unusual and may be hazardous.
Current interest in developing novel blood tests (Fibrotest) or scans (e.g.
Fibroscan) to predict liver fibrosis/cirrhosis

Management of cirrhosis
 Slow or reverse progress (e.g. by specific treatments aimed at aetiology)
 Screen for and potentially prevent complications (e.g. look for varices by
endoscopy, HCC with regular US & AFP, low index of suspicion for SBP by
doing diagnostic paracentesis in ascites)
 Treat complications or their precipitants promptly
 Avoid or treat further insults to the liver (e.g. immunise against HAV)
 Consider orthotopic liver transplantation (OLT)

Lecture 4 - Key Revision

 Be aware of the spectrum of fatty liver disease
 What is fatty change?
 How does alcohol affect the liver?
 What other effects are caused by alcohol?
 What is non-alcoholic fatty liver disease?
 What is hereditary haemochromatosis and what does it cause?
 How is hereditary haemochromatosis diagnosed?
 What are the similarities and differences between autoimmune hepatitis &
primary biliary cirrhosis?
 How is autoimmune liver disease diagnosed?
 What is cirrhosis and how is it classified? What causes it?
 Revise the complications of cirrhosis. How do they affect prognosis?

• Lecture series on diseases of liver and biliary tract prepared April 2011 by:
• John O’Dowd, Department of Pathology, Royal College of Surgeons in Ireland,
Education and Research Centre Beaumont Hospital
• Any suggestions, comments or corrections on these notes welcome on email
• email address <[email protected]>

LIVER, PANCREAS & BILIARY TRACT

Lecture No. 5
John O’Dowd

Outline of Lecture

 Liver tumours
o Classification
o Metastatic liver tumours
o Hepatocellular carcinoma
 Biliary tract and gall bladder tumours
 Pancreatic tumours
o Pancreatic cancer
o Pancreatic neuroendocrine tumours
 Drugs and the liver
 Vascular pathology and the liver
 Liver transplantation
 (Pregnancy and the liver)
 (Liver diseases in infancy and childhood)

The latter two topics are included for future reference in Obstetrics and
Paediatrics

Lecture No. 5 - Learning Objectives

•Be able to classify liver tumours and understand the relative importance of
metastatic liver tumours and primary hepatocellular carcinoma
•Understand where hepatocellular carcinoma is common, in what context it
commonly develops and how we screen for it
•Understand what is meant by cholangiocarcinoma?
•Know whether pancreatic cancer is common, how it presents, how it is
diagnosed and how it is treated
•Know whethet drugs cause liver disease and how liver disease affects drug
prescription
•Understand the mechanism and significance of paracetamol self-poisoning

LIVER TUMOURS
This basic framework can be used when considering tumours (or possible
tumours) in any given organ. However, always highlight the common or clinically
significant entities – that is, be sensible.

 Non-neoplastic versus true neoplastic lesions

o Non-neoplastic lesions may mimic tumours either on imaging or
at surgery, e.g. cysts, hamartomas or abscesses.
For example, bile duct hamartomas common in liver (and may
raise the question whether they’re a tumour for surgeons at
operation)
 Benign versus malignant neoplasms
 Primary versus secondary malignancies
 Different types of benign or malignant primary neoplasms
o Possible different types of primary neoplasm will depend on the
possible/likely tissue types in the organ involved
o Obviously: in any given organ, some types of neoplasm or
malignancy are much commoner than others – highlight these

PRIMARY LIVER TUMOURS

 Benign
o Hepatic adenoma (= liver cell adenoma)
 Very rare, a/w anabolic steroids, (OCP), prone to rupture
o (Bile duct adenoma, very rare)
o Haemangioma – example of a non-epithelial benign tumour
o Focal nodular hyperplasia – lesion of regenerative origin most
likely but resembles a benign tumour radiologically

 Malignant
o Hepatocellular carcinoma (= liver cell carcinoma, hepatoma)
o Intrahepatic cholangiocarcinoma (intrahepatic bile duct
adenocarcinoma)
 o (Haemangiosarcoma, very rare example of malignant tumour of
non-epithelial origin, historical interest only, a/w manufacture
PVC)

SECONDARY LIVER TUMOURS

 Metastases to liver commonest liver tumour by far in Europe/N. America
 Secondaries from carcinoma elsewhere - GI tract (large intestine, stomach,
oesophagus, pancreas, biliary tract, gall bladder), lung, breast, ovary
 This is typically what is meant in this country when people might say there is
“cancer in the liver”
 Other disseminated malignancies may also involve liver - lymphoma,
leukaemia
 Metastases may cause cholestatic effects:
o Early and localised, leads to few symptoms but raised alkaline
phosphatase may be a marker of a local infiltrating lesion causing local
obstruction
o Later on when extensive, possibility of raised bilirubin, late jaundice
 Generally poor outlook with metastatic tumours – but try and identify primary
site of origin of tumour
 Disseminated metastatic disease may be effectively treated to improve
outcome or palliate
 Surgical resection of colorectal metastases now routine in selected patients

HEPATOCELLULAR CARCINOMA
 Northern Europe/North America rare (except in certain ethnic groups and in
patients with cirrhosis)
 Common in SE & E Asia/parts of Africa
 Most cases associated with cirrhosis or advanced chronic hepatitis (>90%)
 Estimated that 3% of cirrhotics develop HCC/year, probably higher rate in
high incidence areas
 Higher rate in some types of cirrhosis than others (chronic viral, HFE>AIH,
PBC)
 May develop in 30s/40s in endemic HBV areas in a/w with chronic HBV
cirrhosis or even prior to cirrhosis a/w chronic HBV hepatitis
 May form single mass or be multifocal in cirrhotic liver
 Metastases not usual
 Future hope: HBV vaccination will reduce high incidence in endemic HBV
areas

Presentation of HCC

 High incidence areas: may present simultaneously or even before cirrhosis,

often in 25-45 year olds with chronic HBV infection from an early age
 Low incidence areas patient typically >50 years old, may present with:
o Sudden decompensation in patient with known cirrhosis (HE, ascites)
o Abdominal pain, weight loss, mass, bleed into peritoneum
o Rare a/w para-neoplastic syndromes (hypoglycaemia, polycythaemia)

Diagnosis

 Clinical features (may be difficult to pick up on background of chronic liver

disease, hence reliance on screening in known cirrhotics)
 Radiology (ultrasound every 6/12 for screening, may require dynamic MRI/CT
studies with contrast for definitive diagnosis)
 Blood alpha-fetoprotein (AFP)
o Tumour marker, produced by fetal liver, indicative of tumour cell de-
differentiation (NB: also produced by germ cell tumours of testis as
evidence of yolk sac differentiation)
o High/rising levels of AFP diagnostic in right context, lower levels less
specific as similar low level AFP elevations also found in hepatitis
flares
o Screen every 6/12 in known cirrhotics

Treatment

 Surgery can be curative, but surgery unusual because of extent of tumour

(size or multifocality) or condition/co-moribidities of patient (e.g. advanced
cirrhosis) in most cases
 Other local treatments e.g. chemo-embolisation of tumour, radiofrequency
ablation
 Systemic chemotherapy poor results
 Liver transplantation occasionally an option

Prognosis typically poor because of stage of tumour at presentation and co-

morbidities, most dead within one year, survival typically 6-18 months.

Screening patients at high risk for HCC: US, AFP at 6/12 intervals in those with
stable/uncomplicated cirrhosis – try and identify early/operable tumours

Aetiology of HCC
 Cirrhosis/chronic liver disease – but risk of HBV/HCV/haemochromatosis-
associated cirrhosis > others types such as AIH/PBC-associated?
 Chronic HBV/HCV without cirrhosis – do not have classic oncogenes but may
have some pro-oncogenic effect?
 Aflatoxins - fungal contaminants of food stores, ?increase susceptibility in
those areas already with endemic chronic viral hepatitis

CHOLANGIOCARCINOMA
 Adenocarcinoma of bile ducts, either intrahepatic or extrahepatic
 Intrahepatic cholangiocarcinoma accounts for <10% primary liver malignancy
 Most tumours peri-hilar (60%, i.e. at hilum of liver), specifically called Klatskin
tumours if they are associated with obstruction at the bifurcation of the
common hepatic duct
 Remainder either intrahepatic or in distal common bile duct

Aetiology:

 Percentage associated with primary sclerosing cholangitis (typically with

background UC) – about 20% of patients with PSC develop
cholangiocarcinoma
 Other factors: congenital biliary tract abnormalities (e.g. choledochal cyst),
Clonorchis liver fluke infection, exposure to Thorotrast (x-ray contrast medium
but banned since 60s)

 Relatively rare tumour

 Definitive diagnosis may be difficult, hard to get at to biopsy
 On background of PSC, may be difficult to differentiate benign from malignant
stricture (e.g. at ERCP)
 Outcome usually poor, liver transplantation not appropriate
 Palliation of obstruction via placement of stent at ERCP
 Typically presents late with cholestasis, weight loss and abdominal pain,
similar to advanced pancreatic cancer

GALL-BLADDER ADENOCARCINOMA
 Affects <1% of those with gall-stones but:
 >80% of cases of gall-bladder adenocarcinoma associated with gall-stones,
stones typically present for >40 years
 Particularly strong association with chronically damaged gall bladders
showing calcification (so-called “porcelain gall-bladder”, also associated with
gall bladder “polyps” seen on U/S >1cm diameter
 F>M, older age group, relatively rare tumour
 Typically presents late, vague non-specific symptoms similar to advanced
pancreatic cancer, outlook poor

 Note that ultrasound often detects polypoid lesions in the gall bladder, leading
to the clinical question “could these be adenomas/carcinomas?”
 If these gall bladder polyps are small (<5mm) and don’t grow progressively,
they are highly likely to be non-neoplastic lesions related to polypoid
protrusions of cholesterol-laden gall bladder mucosa into the gall bladder
lumen (so-called cholesterol polyps) and hence prophylactic cholecystectomy
is unnecessary.
AMPULLARY CARCINOMA

 Rare adenocarcinoma derived from structures of ampulla itself rather than

from distal bile duct, adjacent pancreas or adjacent duodenum
 Histologically resemble intestinal tumours rather than pancreatico-biliary
tumours
 May present relatively early with bile duct obstruction/obstructive jaundice
 Therefore, better 5-year survival following resection compared to any other
hepato-biliary cancer
 May be associated with familial adenomatous polyposis/adenomatous
polyposis coli (FAP/APC) – commonest tumour in FAP once colon resected

PANCREATIC TUMOURS
 EXOCRINE PANCREAS
o Malignant: pancreatic (ductal) adenocarcinoma relatively common
= “pancreatic cancer”
o Cystic pancreatic neoplasms much rarer, increasing identification with
imaging – some types entirely benign, others intermediate with low but
defined malignant potential – complicated area

 ENDOCRINE PANCREAS
o Pancreatic endocrine/neuroendocrine tumours rare
o Behaviour sometimes difficult to predict (benign vs malignant)
o Association with parathyroid hyperplasia and pituitary adenomas in
Multiple Endocrine Neoplasia type 1 syndrome (MEN 1)

PANCREATIC CARCINOMA
 Adenocarcinoma arising from pancreatic ducts
 Common - 5th/6th by rank of cancer deaths
 M>F, associated with smoking (1.5x relative risk compared to non-smokers),
DM (2x), chronic pancreatitis
 80% >60 years, rare <40 years, 60-70% from head, rest from body & tail
 Spread
o Direct local: peritoneum, duodenum, bile duct
o Lymph nodes & to liver

Symptoms

 Anorexia, vague abdominal discomfort, weight loss (i.e. vague)

 Obstructive jaundice (only sometimes, esp. tumours in head, often not early)
 Later abdominal pain, radiating to back, late palpable mass
 Migratory thrombophlebitis (Trousseau’s sign - rare)
o Superficial and deep venous thrombosis

Diagnosis

 CA 19-9 serum marker for pancreatic and biliary cancer

o Not especially sensitive or specific, not suitable for screening/treatment
decisions
o Elevation may also be a/w biliary obstruction from any cause
 Radiology (CT), sometimes fine needle aspiration via EUS
 Avoid unnecessary investigation in majority

Prognosis

 5 year survival <2%, most patients die within 1 year

 Of 10-15% of patients suitable for surgery, only 10-25% 5 year survival

Treatment

 10-15% suitable for radical surgery, pancreatico-duodenectomy (Whipple’s

operation), relatively high operative mortality, significant morbidity
 Majority: palliation via stenting (ERCP or surgical by-pass), analgesia,
palliative chemotherapy

PANCREATIC (NEURO)ENDOCRINE TUMOURS

All very rare, classified by polypeptide hormone product, hormone product
sometimes causes clinical effects. All difficult to diagnose, potentially difficult to
localise, sometimes multiple
 Insulinoma (up to 60%)
o Hypoglycaemia induced by fasting or exercise, relieved by glucose
o Usually benign behaviour (all other types of pancreatic neuro-
endocrine tumours have a significant rate of metastasis)
 Gastrinoma (20%): Zollinger-Ellison syndrome high gastric acid output,
multiple peptic ulcers (stomach, duodenum, jejunum), diarrhoea, most
gastrinomas a/w ZE syndrome extra-pancreatic (e.g. in duodenum)
 Non-functioning (15-30%)
 All other types very rare:
 Glucagonoma: A/w excess glucagon - diabetes mellitus, characteristic skin
rash, diarrhoea
 VIPoma: A/w excess vasoactive intestinal peptide - watery diarrhoea,
hypokalaemia, alkalosis
 Somatostatinoma

Note - suspect pancreatico-biliary malignancy if patients present with

cholestasis/obstructive jaundice + weight loss and abdominal pain

OVERVIEW OF HEPATO-PANCREATICO-BILIARY
TUMOURS
Indicative figures from NCRI (for lung, pancreas, liver, gall-bladder, biliary tract –
incidence figures roughly equal mortality figures because most patients who get
the disease, die of it – not the case for colorectal or breast cancer, where
significant numbers of those who get the disease are long-term survivors):

 Pancreas 350 cases/yr, M=F

 Gall bladder 40/yr, F>M
 Cholangiocarcinoma 70/yr, F>M
 Liver 70/yr, M>F
 Lung 1600/yr - Colorectal 1800/yr - Breast 1700/yr

DRUGS & THE LIVER

 Liver has central role in drugs metabolism/excretion
 First step in liver metabolism is via cytochrome P450 system (to active or
inactive forms, depending on drug), second is conjugation for excretion
 Liver disease (especially chronic liver disease) may alter drug metabolism
o May make them more active or less active depending on normal
patterns of metabolism
o Check BNF in case caution necessary in prescribing a drug when
there is co-existing chronic liver disease

 Administration of one drug may induce or inhibit the metabolising enzymes in

the liver and hence may alter metabolism of other drugs using similar
metabolising pathways
 o Importance of drug interactions involving liver metabolism

 All types of liver disease may be caused by drugs (this is termed iatrogenic
liver disease)

o Importance of drug history in most types of liver disease

o Including OTC and herbal medications and recreational drugs

Adverse drug reactions classified as follows:

Type 1 - predictable, dose related (usually due to the normal inactivating

pathway becoming saturated)
Type 2 - idiosyncratic, not dose-related (typically associated with either
hypersensitivity reaction [and therefore second exposure] or due to aberrant
metabolism)
Identify drug reactions/toxicity

 Not straightforward, because there may be multiple medications, co-existing

disease from other causes, other possible causes. Critical question: is there a
temporal relationship?
o No reaction before drug administered
o Reaction identified after drug administered
o Reaction improves after drug withdrawn (re-challenge to reproduce
drug toxicity usually hazardous and hence very unusual)

Halothane classic example of type 2 hypersensitivity adverse reaction

 1/30,000 following second dose, acute hepatic necrosis, risk of FHF

Paracetamol classic and common example of type 1 adverse reaction

 Remarkably safe drug at therapeutic doses (paracetamol = acetaminophen)

 Potential for toxicity in overdose underestimated, hence a common cause of
overdose and overdose-related death, not always with suicidal intent

 Paracetamol metabolism at therapeutic doses

o 90% conjugated with glucuronate and sulphate in liver and excreted
o 5% excreted in urine unchanged
o 5% metablised by cytochrome P450 in liver to toxic NAPQI
o NAPQI mopped up and rendered non-reactive by glutathione stores in
hepatocytes
 Metabolism in overdose
o Conjugation overwhelmed, more metabolised to toxic NAPQI in liver
o Glutathione stores in liver cells become depleted, reactive NAPQI
accumulates and causes hepatic necrosis, zone 3 especially
o Risk of fulminant hepatic failure
 Treatment: recognise potential gravity, prompt treatment
 o If within 4hrs, activated charcoal to prevent absorption in gut
o Prompt treatment to avert toxicity, if within 8-10hrs, death/FHF rare
o Symptoms may not be marked early on, if patient unaware of
significance of paracetamol toxicity, may delay seeking medical advice
with disastrous consequences
o N-acetylcysteine (-SH donor) administered to replenish glutathione
stores and reduce NAPQI levels, totally effective within 8-10hrs
 Assessment: of risk of serious hepatotoxicity based on relationship between
time since ingestion and blood level (see nomogram illustration in slide
presentation)

 Alcohol related chronic liver disease: sensitised to chronic paracetamol

toxicity, occurs with repeated or supra-therapeutic doses (i.e. >2g/day), at
lower doses than those causing acute toxicity in patients with normal livers

Patterns of liver disease secondary to drugs

 Multiple possibilities – consult text books.

 Although liver toxicity may occur relatively infrequently in any single individual
taking some drugs, because some drugs are commonly prescribed, such
reactions may appear with some frequency in clinical practice. Elevated
transaminases commonest manifestation of such toxicity (e.g. with NSAIDs,
statins, antibiotics)
 For any given pattern of acute or chronic liver disease or liver injury
presenting, there are possible drug causes which should be considered in
the differential diagnosis, e.g.

 Acute necrosis/risk of FHF Paracetamol, halothane, drugs a common

cause of FHF
 Acute hepatitis Isoniazid, methyldopa, NSAIDs
 Elevated transaminases Statins, antibiotics, antiepileptics, NSAIDs
 Chronic hepatitis Methyldopa, isoniazid, nitrofurantoin
 Cholestatic reactions Chlorpromazine, erythromycin, antibiotics,
OCP, drugs a relatively rare cause of
jaundice
 Fatty change (usual type) Amiodarone, methotrexate, HAART
 Microvesicular fatty change Tetracycline in overdose, valproate
 Granulomas Sulphonamides
 Fibrosis & cirrhosis Methotrexate
 Budd-Chiari syndrome OCP
 Veno-occlusive disease High dose chemotherapy
 Liver adenoma OCP, anabolic steroids

VASCULAR PATHOLOGY & THE LIVER

 Infarction rare (trauma to hepatic artery likely cause) because liver protected
by dual blood supply

 Obstruction of main hepatic vein or branches or intrahepatic IVC = Budd

Chiari syndrome, rare
o Associations: hrombotic states (e.g. myeloproliferative disease,
inherited pro-thrombotic states, rarely OCP), hepatoma, trauma
o Causes abdominal pain, acute portal hypertension, ascites, FHF

 Obstruction/fibrosis of microscopic hepatic vein branches = veno-occlusive

disease, very rare and specific associations
o High dose chemotherapy/radiotherapy (BMT conditioning), toxicity
from herbal medications. Very rare outside of these contexts

 Chronic passive venous congestion of liver

o Most marked around central veins (‘nutmeg liver’ appearance to liver at
autopsy)
o Associated with right heart failure: congestive heart failure or cor
pulmonale, mitral stensosis
o Extreme changes in tricuspid incompetence or constrictive pericarditis,
very uncommon
 Relatively common cause mild/minimal biochemical abnormality (raised AST,
ALT, bilirubin), typically not clinically relevant

 Ischaemic injury to liver

 Typically associated with acute circulatory failure (that is, shock/hypotension)
although changes in other organs usually more prominent in this situation
 Context is usually diagnostic
 If liver already has chronic passive venous congestion or portal hypertension,
more susceptible to ischaemic injury
 Significant ischaemic injury to liver involves zone 3 especially (transaminases
may be dramatically elevated)

Hospitalised patients who develop dramatically elevated transaminases –

ischaemic injury or drugs the typical causes

PREGNANCY & THE LIVER

See Obstetrics
Possible liver problems during pregnancy – are they pregnancy-related or not?

 Pre-existing liver disease (e.g. chronic HBV) may be diagnosed by

screening during pregnancy
  Liver blood tests altered by normal pregnancy (alkaline phosphatase
elevated, albumin decreases slightly)
 Liver blood tests may become dramatically abnormal a/w hyperemesis
gravidarum
 Acute hepatitis/jaundice may present during pregnancy, commonest
cause acute viral hepatitis (pregnancy may be a/w more adverse
outcome)
 Specific rare or very rare pregnancy-associated liver conditions:

 Cholestasis of pregnancy/obstetric cholestasis

o 3rd, sometimes 2nd trimester, presents with itch and jaundice
o 20% of jaundice in pregnancy, important to exclude other causes
o Uncommon, 0.5% of pregnancies
o ?steroid-related, often recurs in subsequent pregnancies, shares a
predisposition to intrahepatic cholestasis induced by OCP
o Risk to fetus of prematurity/stillbirth, deliver as soon as possible

 HELLP syndrome
o Haemolysis, Elevated Liver enzymes, Low Platelets
o Develops in 20% of those with pre-eclampsia
o Develops in third trimester, sometimes post-partum
o A/w DIC, placental abruption, significant risk neonatal mortality
o Treatment is delivery if feasible

 Acute fatty liver of pregnancy

o Typically late 3rd trimester
o Extremely rare, significant risk FHF, cause of occasional maternal
death
o Microvesicular fatty change on histology, associated with inherited
defect in mitochondrial enzyme involved in fatty acid metabolism
o Treatment is delivery of baby and intensive hepatology support

LIVER DISEASE IN NEONATAL PERIOD/CHILDHOOD

See Paediatrics/Neonatology

 Unconjugated hyperbilirubinaemia
o Mild common = physiological jaundice
 Immaturity of liver conjugating enzyme
 Usually resolves quickly as conjugation enzyme mature
o Significant hyperbilirubinaemia may require treatment, jaundice may
not resolve
 Associated with prematurity, significant haemolysis (e.g. Rhesus
incompatibility) or other factors affecting bilirubin excretion
 Marked unconjugated hyperbilirubinaemia, risk of bilirubin toxicity
 (encephalopathy, chronic neurological damage = kernicterus), now very rare
 Treatment phototherapy, occasionally exchange transfusion

 Neonatal cholestatic jaundice very rare, generally serious

 Biliary atresia/abnormalities - secondary liver damage results over a long
period of time (secondary biliary cirrhosis)
 Neonatal hepatitis - A1AT deficiency, ToRCH infections, in-born errors of
metabolism may all cause this

Reye’s syndrome

 Increasingly rare, first observed in children <10 with URTI given aspirin
 Case mortality of 25%, convulsions, FHF
 Microvesicular fatty change liver and brain on histology at autopsy
 Hence: only paracetamol now given to children under 10 as anti-pyretic
 Is Reye’s really an inherited abnormality of fatty acid metabolism?

 In-born errors of metabolism

 Very complex area: managed by paediatrician with interest in metabolic

disorders (Temple St)
 Abnormal substance (type depends on disease) may be stored when
excessive in liver
 Many diseases therefore often associated with liver inflammation, fibrosis,
cirrhosis
 Often associated with CNS effects due to abnormal storage in CNS also

 Cystic fibrosis (see Lecture Six)

LIVER TRANSPLANTATION
 70% 5 year, 50% 1 year survival

 Indications
o Cirrhosis = end stage chronic liver disease - PBC, PSC, auto-immune
hepatitis, alcohol-related, chronic HBV/HCV (>50%)
o Fulminant hepatic failure – paracetamol by far commonest cause
o Malignancy rare
o Childhood - biliary atresia and other abnormalities, metabolic disorders
(in born errors of metabolism)

 Livers do not need to be HLA-matched (blood group only)

 Problems
o Selection of patients, decisions regarding listing for transplant
 o Organ supply
 Living donor
 Split-liver cadaveric graft
o Rejection
o Technical surgical problems
o Immunosuppression (drugs toxic, increase risk of infection, second
malignancy)
o Disease recurrence (especially viral)

 Orthotopic because transplanted liver placed in same body site as native liver
which has been removed (unlike kidney transplant)

Lecture 5 - Key Revision

 Be able to classify liver tumours
 Know that metastatic tumours are the commonest type in this country
 Where is primary hepatocellular carcinoma common and why?
 Is hepatocellular carcinoma related to cirrhosis?
 What is cholangiocarcinoma?
 Know that pancreatic carcinoma is common and has a poor prognosis,
how it presents and how it is treated
 Know that drugs are an important cause of many kinds of liver disease
(predictably related to dose or related to idiosyncratic reactions)
 How would you identify a possible drug reaction?
 Know that liver disease may modify drug prescription
 Know the importance and mechanism of paracetamol self-poisoning

• Lecture series on diseases of liver and biliary tract prepared April 2011 by:
John O’Dowd, Department of Pathology, Royal College of Surgeons in Ireland,
Education and Research Centre Beaumont Hospital
• Any suggestions, comments or corrections on these notes welcome on email
• email address <[email protected]>

LIVER, PANCREAS & BILIARY TRACT

Lecture No. 6
John O’Dowd

Outline of Lecture
  Gall stones
 Complications of gall stone disease
 Extrahepatic cholestatsis/obstructive jaundice
 Acute pancreatitis
 Chronic pancreatitis
 Pancreatic pseudocyst
 Cystic fibrosis

Lecture No. 6 – Learning Objectives

 Know the frequency and significance (or otherwise) of finding gall stones
 If gall stones do cause symptoms, know how his happens
 Understand what is meant by acute cholecystitis
 Know the causes and effects of extrahepatic bile duct obstruction
 Know the common causes and presentation of acute pancreatitis and
chronic pancreatitis
 Understand the significance of testing for amylase
 Understand the consequences of severe acute pancreatitis and how they
may endanger life
 Know what is meant by a pancreatic pseudocyst
 Understand the nature of the defect in cystic fibrosis, what organs the
disease affects and how

Revise anatomy of normal biliary tract

Normally, continuous flow of bile from liver to duodenum - via right and left
hepatic duct, joining to form common hepatic duct, joined by cystic duct (which
drains gall bladder) to form common bile duct. Common bile duct and pancreatic
duct share an outflow at the ampulla of Vater (duodenal papilla) in 70% of people

NORMAL GALL-BLADDER
 Gall bladder stores and concentrates bile made by liver
 Eating stimulates CCK release, which stimulates gall bladder contraction and
release of concentrated bile via cystic duct into CBD and thus small intestine
 Gall bladder function is not vital – few problems post-cholecystectomy related
to loss of function

 Anatomical variants – where cystic duct joins rest of biliary tract or presence
of accessory ducts and variations in blood supply - important for surgeons to
know these
 Bile contents
o Bile salts and phospholipids (detergent action required for absorbing
 fats and fat soluble vitamins ADEK in small intestine). Note that bile
salts are conserved via an enterohepatic circulation whereby most are
reabsorbed in the terminal ileum and brought back to the liver via the
portal vein for re-use.
o Excreted substances: cholesterol, bilirubin, calcium salts, copper
 Cholesterol remains in solution in bile by forming micelles with bile salts – but
solution may be unstable with risk of cholesterol precipitating

GALLSTONES
 Easily identified with ultrasound and found to be common, frequency varying
with population, age and gender – 10% or more of adults?

 Stones formed from bile constituents (+/- calcium)

o >80% predominantly cholesterol, may be mixed in composition
 related to inherently ‘unstable’ nature of bile solution
o <20% predominantly bilirubin
 ‘black’, associated with haemolysis, cirrhosis
 ‘brown’, associated with biliary infection or parasites

 10% only of gall stones contain enough Ca to be radio-opaque on plain x-ray

 Cholelithiasis = stones in gall-bladder, very common, may move from there to

CBD

 Choledocholithiasis = stones in common bile duct, usually pass into CBD from
GB (i.e. secondary to gall stones, 85%) but may form in CBD de novo (i.e.
prmary, 15%).

 Asymptomatic choledocholithiasis found in 5% of routine cholecystectomy

 However, if stones retained in CBD, high frequency of subsequent problems

 The assessment and complications of gall-stones form a significant workload:

 Non-acute upper abdominal pain (the differential diagnosis for which includes
symptoms related to gallstones) accounts for at least 5% of general surgery
OPD visits (half of whom may have stones, where the question then
becomes, is their symptomatology likely related to the gall stones?)

 20% of adult elective general (abdominal) surgery is related to gallstones

Predisposing factors for gallstones

 Female (16% of white US women versus 9% of men)

 Age (age more important than gender: men at 60 more commonly have
stones than women at 40)
 Obesity, high fat/low fibre diet but also sudden weight loss
 Geography and race (Native Americans extremely prone to gallstones)
 HRT, pregnancy, not the Pill
 Bile salt depletion (Crohn’s disease affecting ileum, ileal resection)
 High blood lipids, clofibrate, DM
 Cirrhosis (a/w reduced bile salt secretion)
 Haemolysis (typically bilirubin stones)
 Parasites in biliary tract (typically pigmented stones)

Pathogenesis

 Altered bile composition (“lithogenic” bile = stone-forming bile), precise

mechanism unexplained, favours formation of cholesterol stones
 Starts with tendency to crystal nucleation
 Continues with tendency for stones to grow (related to sluggish/static gall-
bladder, worse if gall bladder wall damaged already by previous stone-related
inflammation)
 Stones form in sequential episodes over long period of time, 11 years
average age of stones
 Big stones can obstruct the gall bladder (and hence may cause acute
cholecystitis) but smaller stones may be able to migrate into the common bile
duct where they may cause extrahepatic biliary obstruction
 “Lithogenic” bile may also form biliary sludge or tiny stones (microlithiasis)
which can cause complications in some causes

PATHOLOGICAL EFFECTS OF GALL-STONES

 Most (>80%) gall stones are asymptomatic or incidental
 Only 20% followed up over 15 years develop symptoms (1-3%/yr)

 Biliary pain (= biliary colic)

 Acute cholecystitis and its complications
 Stones moving to (or more rarely, forming in) CBD and associated with
common bile duct obstruction:
o Obstructive jaundice (extrahepatic cholestasis)
o Ascending cholangitis
o Acute pancreatitis
 Mirizzi syndrome (rare, obstruction of CBD by extrinsic compression on wall
of CBD from impacted stone in neck of GB)
 Gall bladder adenocarcinoma – see lecture 5, low overall risk per individual
with long-standing gall stones
 Biliary colic most common symptom specifically related to gall stones –
however, may be difficult to confidently diagnose.
 Non-specific upper GI symptoms and gallstones are both common and often
co-exist, the question therefore arises is one related to the other? Other
symptoms (some termed “dyspepsia”) have much less specificity for any
particular diagnosis including gallstone-related disease, e.g. post-prandial
fullness, early satiety, flatulence, bloating, belching, fatty food intolerance,
epigastric burning

BILIARY COLIC
 RUQ/epigastric pain of moderate severity, radiating round to back, may also
be interscapular/right shoulder, steady crescendo pattern (i.e not truly colicky)
 Last <4hours, may develop after an interval following eating fatty food
 Visceral pain due to distension following obstruction of cystic duct by stone
 No peritoneal inflammation, so no tenderness/guarding on abdominal exam
 No fever, may be nauseated and sweating, WCC normal
 Pain relieved as stone spontaneously falls backwards

 70% of patients with biliary colic have recurrent symptoms within 2 years and
1-3% subsequently develop significant complications such as acute
cholecystitis or acute pancreatitis.

 Moderately severe pain: differential diagnosis includes PUD, MI, acute

pancreatitis, oesophageal spasm, acute hepatitis

 Biliary colic is the only symptom of mild/moderate severity reliably related to

gallstone-related disease and therefore must be carefully sought. Problem is
certainty in diagnosis of biliary colic. However, confident diagnosis of biliary
colic is an indication for cholecystectomy on the basis of risk of subsequent
more severe complications.

ACUTE CHOLECYSTITIS
 >90% associated with gall-stones, causing:

 Cystic duct obstruction, resulting in:

o Stasis/over-concentration of bile and resulting acute inflammation of
gall bladder
o Sterile initially, but can get secondary infection

 Symptoms:
o Typically background of previous biliary colic
o Fever, severe RUQ pain >24hrs, systemically unwell
o No jaundice – if jaundice, consider CBD obstruction by stone or a/w
rare Mirizzi sybdrome
 o Peritoneal inflammation causes tenderness, guarding and rebound
RUQ (positive Murphy’s sign)
o High WCC
o Ultrasound and/or CT typically diagnostic

 Initial treatment fluids, analgesia, antibiotics

 Treat with cholecystectomy in same admission or within 6 weeks (if delayed
longer, higher % recurrence of acute cholecystitis or other complications)

 Complications of acute cholecystitis may occur in 10-20%

o Empyema - unrelieved obstruction with pus filling gall-bladder

o Mucocele - unrelieved obstruction, gall-bladder enlarged but sterile,
distended with mucus
o Necrotizing inflammation with risk of perforation
o Perforation may cause localised pericholecystic abscess or
generalised biliary peritonitis (rare)
o Necrotizing inflammation with adhesion to duodenum may result in
fistula formation (cholecystoduodenal fistula)
o Fistula may be associated with passage of stone into small intestine
and risk of gallstone obstructing terminal ileum, causing gallstone ileus

 Acalculous acute cholecystitis <10% of cases (no stones present), associated

with marked biliary stasis, typically in very unwell patients (e.g. those with
septic shock, hypotension, burns, major trauma)

COMMON BILE DUCT OBSTRUCTION by GALLSTONES

 Causes extra-hepatic cholestasis/obstructive jaundice (=”surgical jaundice”)
 Stones can move from gall-bladder to CBD or (more rarely) form in CBD, may
pass ultimately but can still cause symptoms in transit.

 Symptoms:
o Obstructive jaundice - painful, intermittent, elevated alkaline
phosphatase/GGT, dilated ducts on imaging, risk of infection
o Ascending cholangitis - obstruction with secondary infection (high
fever, RUQ pain, jaundice = Charcot’s triad)
o Acute pancreatitis (if stone obstructs distal CBD)

CHRONIC CHOLECYSTITIS
 Pathological finding in surgically-removed gall bladders, always associated
with gallstones, chronic structural response to repeated attacks of obstruction/
 inflammation
o Shrunken, fibrotic gall-bladder
o Evidence of previous obstruction - mucosa atrophied, muscle
thickened, diverticula
 No correlation of these pathological findings with specific symptoms

GALL-STONE TREATMENT
 If symptomatic (either biliary colic or complications), cholecystectomy
 If incidental finding, observe as only 20% long term risk of symptoms

 Clinical difficulty may be in confidently identifying biliary colic and

distinguishing it from other non-specific upper GI disturbances

 Patient selection for cholecystectomy not a precise science

o Many patients may still have some symptoms post-op
o Some patients may have same symptoms post-op, termed:
o ‘Post cholecystectomy syndrome’
o ?Wrong diagnosis
o Persisting obstruction following cholecystectomy – possibility of
recurrent/retained stone in CBD
o Suspected retained stones in CBD – difficult management problem

 If choledocholithiasis – either duct clearance of stones and sphincterotomy by

ERCP prior to surgery or duct clearance/bile duct exploration at time of
cholecystectomy

 Medical treatment of gallstones rare (bile salt dissolution, lithotripsy)

Cholecystectomy

 Open or laparoscopic, laparoscopic now much commoner because:

o Shorter hospital stay, lower mortality (0.1 vs. 0.5%)
o Lower costs? Not overall, because rise in rates of operation
o Risks: more frequent biliary tract injury, retained CBD stones
o “Learning curve” demonstrated for new operators

CAUSES OF EXTRA-HEPATIC DUCT OBSTRUCTION

 Gall-stones in common bile duct
 Adenocarcinoma of pancreas or ampulla
 Bile duct adenocarcinoma in extrahepatic duct
 Benign stricture (post-operative, post-ERCP or related to PSC)
 Mass outside CBD/CHD compressing duct
o Mirizzi syndrome (stone in neck/cystic duct of GB compressing duct)
o Primary tumour or metastases in lymph nodes

 Courvoisier’s law: clinical assessment of bile duct obstruction

o If gall-bladder palpable, suspect malignancy
o If gall-bladder not felt, suspect gall-stones (because gall-bladder
shrunken and rigid due to chronic inflammation related to gallstones,
therefore can’t expand secondary to extrahepatic duct obstruction)

 Investigation of cause of extra-hepatic duct obstruction

o Ultrasound can demonstrate dilated ducts secondary to obstruction
o Ultrasound might identify cause of obstruction, but not good at
visualising lower end of CBD – MRCP, EUS or ERCP better (ERCP
particularly indicated if treatment for obstruction, such as stent or
sphincterotomy, also considered)

Treatment of stones
• ERCP with sphincterotomy +/- stone removal OR
• CBD exploration at surgery when cholecystectomy being performed
(laparoscopic procedure being converted to an open one if necessary)

Treatment of obstructing tumour or stricture

• Curative surgery usually not possible, stent may be placed at ERCP to help
maintain patent CBD

Acute (ascending) cholangitis

 Secondary to obstructed extrahepatic duct, causing biliary stasis with
increased risk of infection, typically by Gram negative bacilli
 Obstructive jaundice, RUQ pain (colicky), fever = Charcot’s triad
 Treatment
o Antibiotics
o Relieve obstruction as matter of urgency

PANCREAS
 Retroperitoneal, posterior abdominal wall, extends horizontally from 2nd part
 of duodenum to spleen
 Head in loop of duodenum, tail adjacent to spleen, body in between
 Two distinct components embryologically and functionally
o Exocrine tissue 98% of bulk: produces digestive enzymes
o Endocrine tissue: islets of Langerhans, different cells produce insulin,
glucagon etc., hormones secreted directly into blood
 Exocrine composed of glandular acini grouped into lobules
o Exocrine secretions drain via small ducts, which then join to form
pancreatic duct
o Pancreatic duct enters duodenum at ampulla of Vater, in majority of
people a/w CBD
o Enzymes secreted as inactive form, require activation by gut enzymes
 Heterotopic pancreatic tissue may occasionally be found in stomach,
duodenum or Meckel’s diverticulum
 Anatomical variations not rare (e.g. pancreas divisum - more prone to
disease)

 Main diseases of exocrine pancreas: acute and chronic pancreatitis,

pancreatic cancer, pancreatic pseudocyst

ACUTE PANCREATITIS
 Acute inflammation of pancreas:
 50 cases/million
 Mortality ?5% (higher if severe)
 Acute pancreatitis can recur, severe attack more likely with first attack than
recurrent attacks

Pathogenesis of acute pancreatitis

 Once inflammation initiated, irreversible cascade of effects

 Premature activation of enzymes within pancreas (autodigestion)
 Local inflammatory response (a/w mild, self-limiting disease)
 If severe enough, may trigger systemic inflammatory response syndrome and
extensive local necrosis (a/w severe disease)

80% mild, self-limiting disease

 Oedema and non-necrotizing inflammation of pancreas

20% severe disease

 Necrotizing inflammation of pancreas with necrosis of peri-pancreatic fat

 o Hypocalcaemia (calcium removed from blood by binding to free fatty
acids in necrotic peri-pancreatic fat = ‘saponification of fat’)
o Hyperglycaemia (damage to islets, but often preserved)
o Paralytic ileus
 Systemic inflammatory response syndrome with multi-organ dysfunction
caused by cytokine release and associated with vasodilatation, increased
capillary permeability and DIC
o Massive fluid loss from circulatory compartment, hypovolaemia, risk of
ARDS, acute renal failure, DIC
 Risk of local complications: infection of necrotic tissue, pseudocyst, fistula

Significant mortality a/w severe acute pancreatitis can be conceptually divided

into two phases:
 First phase (first week approximately 50%) a/w SIRS (ARDS, ARF, DIC
etc)
 Second phase (second week on, approximately 50%) a/w extensive
necrosis and associated sepsis

Causes of acute pancreatitis

 Gall stones
 Alcohol
o Together 80%: stones more frequent than alcohol, stones more
common in women, alcohol more frequent in men

 Post-ERCP (5%)
 Idiopathic (10%)
o Some may be associated with biliary microlithiasis or biliary sludge
(tiny microscopic stones or stone-like crystals in bile)
 Miscellaneous uncommon causes (5%)
o Trauma, ischaemia, shock, major surgery
o Drugs (thiazides, azathioprine, HAART + long list)
o Viral (mumps, EBV, CMV, coxsackie)
o Hyperlipidaemia
o Hypercalcaemia
o Hereditary pancreatitis

 Mechanical factors (e.g. stones, ERCP) trigger enzyme activation by

obstruction and concentration of pancreatic juices/reflux of bile and
duodenal fluid into pancreatic duct
 Alcohol has a direct toxic effect on pancreatic lobules, causing activation
of enzymes

Symptoms of acute pancreatitis

 Acute epigastric/a/bdominal pain, radiating to back, often relieved by sitting

 forward, a/w N, V, evidence of shock
 Cause of acute abdomen - presents to surgeons, therefore general surgeons
usually manage acute pancreatitis
 If severe pain, differential diagnosis includes MI, rupture AAA, perforated or
ischaemic abdominal organ

Diagnosis of acute pancreatitis

 Amylase higher than 3X normal is diagnostic

o Amylase is a pancreatic enzyme leaked by the damaged pancreas
o Low level rise on testing does not exclude acute pancreatitis (amylase
rise short-lived, may already have subsided by the time of
measurement)
o Low level rise amylase not specific for acute pancreatitis, also caused
by perforation or ischaemia of gut
o Lipase used in future? More sensitive/specific

 Identify possible cause for acute pancreatitis from history, imaging

 Gall-stones and alcohol abuse can co-exist: liver blood tests may be helpful to
indicate which is significant
 Avoid unnecessary laparotomy
 CT after several days to assess degree of pancreatic necrosis
 Look for evidence/early treatment of systemic complication

Aim: early identification of those with severe attack of acute pancreatitis

for treatment in ICU/HDU

 Difficult to predict course of attack/severity/prognosis at onset. However,

 Mortality from severe acute pancreatitis usually due to either systemic
complications or infection of necrotic tissue
 Scoring systems used to identify bad prognosis within 48 hours of admission
(actually best at excluding those with good prognosis!)
o Examples include Glasgow or Ranson scores, typically include
following features which are scored:
 Age >55, WCC >15, haematocrit to assess fluid loss
 pO2 <8kPa, albumin <32g/l, Ca <2mmol/l, urea >16mmol/l
 Glucose >10mmol/l, AST & LDH high

Treatment: review management of acute pancreatitis

Mild: analgesia, fluids, nil p.o., recover 48-72 hr, identify cause to try and prevent
recurrence (which may be more severe)

Severe: in addition
 Resuscitation if shocked, intensive care to treat systemic complications
 Nutrition important (enteral feeding)
 Antibiotics if necrotic tissue on CT
 If unwell despite antibiotics, consider debridement of necrotic tissue (=
“necrosectomy”, can be surgical, endoscopic, percutaneous)

CHRONIC PANCREATITIS
Ongoing chronic inflammation damaging pancreas, leading to
 Irreversible fibrosis and impaired pancreatic function
 Often no history of a previous attack of acute pancreatitis
 Sometimes recurrent attacks of acute pancreatitis
 Distortion of ductal system: strictures, dilatation and cysts behind strictures,
stone formation within pancreatic ducts, stones often calcified

Causes of chronic pancreatitis

 Alcohol (70%, for some reason, rarely coexists with cirrhosis)

 Idiopathic
 Hereditary pancreatitis
 Childhood causes e.g. cystic fibrosis
o But CF more commonly causes just pancreatic insufficiency
o This is how cystic fibrosis gets its name (fibrotic and cystic chronically
scarred pancreas in chronic pancreatitis a/w CF)

Symptoms of chronic pancreatitis

 Pain (dull, epigastric radiating to back, often unremitting)

o Nausea, vomiting, epigastric tenderness
 Weight loss (consider other causes e.g. pancreatic cancer)
 Steatorrhoea and malabsorption (rarely clinically obvious)
 Diabetes mellitus (40%?), insulin-dependent but brittle, prone to
hypoglycaemia

Diagnosis of chronic pancreatitis

 Early diagnosis difficult, amylase not useful

 Tests of pancreatic function not routine
 Often a diagnosis of exclusion: symptoms, history of alcohol, previous attacks
of acute pancreatitis
 10% may be associated with pancreatic pseudocyst or internal fistula
 Late/advanced stage: abdominal x-ray, CT, ERCP, MRCP, EUS
o Calcified stones, dilated or “beaded” ducts

Treatment of chronic pancreatitis

 Analgesics, but prone to opiate dependence

 Pancreatic enzyme supplements

PANCREATIC PSEUDOCYST
 Accounts for large majority of pancreatic cystic lesions (cystic tumours
uncommon)
 Localised collection of pancreatic fluid in disrupted tissue in or around
pancreas
 Not a true cyst: lining is granulation tissue, not epithelium
 Follows acute or chronic pancreatitis or rarely pancreatic surgery or trauma
 Due to disrupted pancreatic ductal system but most communicate with the
pancreatic ductal system
 By definition, only a pseudocyst if it occurs/persists 4/52 after attack of acute
pancreatitis (before that, acute fluid collection)
 Symptoms and complications:
o Pain/compression from pressure effect
o Risk of infection
o Erosion causing fistula into adjacent organ or cavity (e.g. peritoneum)
or damage to blood vessel
 Following acute pancreatitis: likely to resolve (therefore tend to manage
conservatively if possible) whereas if part of chronic pancreatitis: tend to
persist
 Aspirate or drain by endoscopy or surgery if troublesome

CYSTIC FIBROSIS
 Ireland, relatively common inherited single gene disorder
 Autosomal recessive
 1/2500 births, 1/25 heterozygote carrier
 Aetiology: abnormal regulation of epithelial membrane chloride transport in
ducts of exocrine glands (hence secondarily affecting sodium and water
transport across membranes as a result)
 Defect: cystic fibrosis transmembrane conductance regulator protein
(CFTR), gene on 7q
o Most exocrine secretions in CF patients, too little chloride transported into
fluid therefore also too little matching sodium and water, secretions too
thick
o Exception is sweat: chloride channel in normal people moves electrolytes
in opposite way to make sweat less salt-rich, therefore in CF patients, too
little chloride reabsorbed from sweat, therefore too little matching sodium
reabsorbed
o Basis of sweat test for cystic fibrosis: demonstration of sweat with high
salt levels. Historic test prior to genetic testing.
 Many different mutations in CFTR gene, frequencies depending on population
studied, commonest in Ireland is F508 deletion
 Typical molecular cytogenetic screen involves looking for commonest
mutations in relevant populations
 Moving points: genetic counselling, antenatal diagnosis, gene therapy

Effects of cystic fibrosis

 Chest disease
o Recurrent infections in thick, viscid secretions(Staph. aureus, mucoid
Pseudomonas)
o Highly resistant organisms following multiple events & antibiotics
o Bronchiectasis, lung abscess, pulmonary hypertension, RHF (“cor
pulmonale”) develop
 Pancreatic disease
o Pancreatic insufficiency with malabsorption, steatorrhoea, failure to
thrive
o Chronic pancreatitis with fibrosis and cysts more unusual
 Neonatal - obstruction of GI tract due to ‘meconium ileus’ (blockage of ileum,
narrowest part of SI, by abnormally thick meconium – meconium is the
secretion of the fetal gut, usually passed in the immediate postnatal period)
 Liver - obstruction of bile ducts, with indolent development of secondary
biliary cirrhosis
 Paranasal sinuses with chronic sinusitis, salivary glands obstructed
 Infertility from bilateral absent vas deferens, thickened cervical mucus

 Improving prognosis due to better management of lung problems and

pancreatic enzyme supplementation, survival now into young adulthood
 ‘Late’ heart, infertility and liver complications now seen more frequently

Lecture 6 - Key Revision

 Understand the significance (or otherwise) of gall-stones and their frequency
 Know how symptomatic gall stone disease presents
 Know about acute cholecystitis and its complications
 Know the causes and effects of extra-hepatic bile duct obstruction
 Know the common causes and presentation of acute and chronic pancreatitis
 Understand the significance of testing for amylase
 Be able to describe the effects of severe acute pancreatitis
 Know what is meant by a pancreatic pseudocyst
 What is the defect in cystic fibrosis and what organ systems are affected?

 Lecture series on diseases of liver and biliary tract prepared April 2011 by:
 John O’Dowd, Department of Pathology, Royal College of Surgeons in
Ireland, Education and Research Centre Beaumont Hospital
 Any suggestions, comments or corrections on these notes welcome on email
 email address <[email protected]>