Download Intrahepatic biliary tract disease - Ipswich-Year2-Med-PBL-Gp-2

Liver Pathology
Metabolic liver disease
1. Non-alcoholic fatty liver disease
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Hepatic steatosis in Pts who do not consume excessive alcohol
Includes hepatic steatosis; steatosis accompanied by minor, non-specific inflammation and; nonalcoholic steatohepatitis (NASH)
o First two are generally stable (no significant clinical problems)
o NASH may progress to cirrhosis in 10-20% of cases
Progresses to fibrosis
Metabolic: dyslipidaemia, hyperinsulinaemia, insulin resistance
Pathogenesis: not entirely known, but
o Hepatic fat accumulation
o Hepatic oxidative stress (acts upon the hepatic lipids  peroxidation  release of lipid
peroxides  ROS)
Clinical features: generally asymptomatic with simple steatosis
o Imaging shows fat accumulation in liver  but liver biopsy is most reliable
o Serum AST and ALT are elevated with NASH
o AST/ALT ratio is <1 for NASH but >2 for alcoholic steatohepatitis
o General symptoms: fatigue, right-sided abdominal discomfort (hepatomegaly)
Morphology:
o Steatosis: macrovesicular and microvesicular fat droplets within hepatocytes + hepatic
inflammation, hepatocyte death/scarring
o Steatohepatitis (NASH): steatosis + multifocal parenchymal inflammation (neutrophils,
Mallory bodies, hepatocyte death, sinusoidal fibrosis) + fibrosis of portal tracts and
around terminal hepatic venules  similar to alcoholic steatohepatitis
o Cirrhosis: if cirrhosis develops, the steatosis/steatohepatitis tends to be reduced and
may not be seen
Tx for NASH is to prevent cirrhosis and reverse steatosis
Mx: correct risk factors (eg obesity, hyperlipidaemia), treat insulin resistance
2. Hemochromatosis
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Primary (homozygous-recessive) Vs secondary (due to parenteral administration of iron; also
called haemosiderosis)
o Juvenile hereditary form (HAMP or HJV mutation) is worse than adult hereditary form
(HFE mutation)  HAMP = hepcidin; HJV and HFE encode proteins regulating hepcidin
levels
Disease manifests itself after 20g iron has accumulated
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Micronodular cirrhosis, diabetes mellitus and/or skin pigmentation
Iron accumulation is lifelong but iron deposition causes slow/progressive injury
Males predominate (present earlier because menstruation/pregnancy delays iron accumulation
in women)
Pathogenesis:
o Abnormal regulation of intestinal iron absorption (hepcidin deficiency)
o Toxicity to host tissues due to
 Lipid peroxidation via iron-catalysed free radical reactions
 Stimulation of collagen formation by activation of hepatic stellate cells
 Interaction of ROS and iron with DNA  lethal cell injury, HCC risk
Morphology:
o Haemosiderin deposition (severity: liver > pancreas > myocardium > pituitary gland >
adrenal gland > thyroid/parathyroid > joints > skin)
o Cirrhosis
o Pancreatic fibrosis
o Golden-yellow hemosiderin granules in periportal hepatocyte cytoplasm (progressively
involves rest of the lobule)
o Liver is typically slightly larger than normal, dense and chocolate brown
o Fibrous septa develop slowly  micronodular cirrhosis
o Pancreas: pigmented, diffuse interstitial fibrosis, some parenchymal atrophy
o Heart: enlarge, haemosiderin granules within myocardial fibres, brown colouration of
myocardium
o Skin: pigmentation (due to inc melanin > haemosiderin deposition)
o Acute synovitis
Clinical features:
o Males, rarely obvious before 40yrs old
o Hepatomegaly, abdominal pain, skin pigmentation, deranged glucose homeostasis/frank
diabetes mellitus, cardiac dysfunction, atypical arthritis, hypogonadism
o Death from cirrhosis or cardiac disease or HCC
o Tx does not remove risk of HCC
o Most Dx is made during subclinical, precirrhotic stage due to routine serum iron
measurements (as part of other diagnostic workup)
o Tx: regular phlebotomy
Haemosiderosis due to ineffective erythropoiesis  excess iron due to transfusion and inc
absorption
3. Wilson Disease
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Autosomal recessive disorder with mutated transmembrane copper-transporting ATPase on
hepatocyte canalicular membrane  leads to
o Impaired copper excretion into bile
o Failure to incorporate copper into ceruloplasmin
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o Inhibits ceruloplasmin secretion into the blood
Toxic accumulation of copper (mostly liver, brain, eye)
Pathogenesis: copper  ROS formation  latent period  sudden onset of critical systemic
illness
o Non-ceruloplasmin-bound copper spills into circulation  haemolysis and other
pathological changes
Morphology:
o Hepatic changes range from minor to massive (steatosis, vacuolated nuclei, focal
hepatocyte necrosis, acute hepatitis are all possible)
o Chronic hepatitis: exhibits moderate – severe inflammation and hepatocyte necrosis 
features of macrovesicular steatosis, vacuolated hepatocellular nuclei, Mallory bodies
 progresses to cirrhosis
o Can have massive liver necrosis (indistinguishable from viral or other causes)
o Brain: toxic to basal ganglia (atrophy, cavitation)
o Kayser-Fleischer rings
Dx based on decrease in serum ceruloplasmin, increase hepatic copper content, increased
urinary copper excretion
Tx: long-term copper chelation therapy, + liver transplant
4. a1-antitrypsin deficiency
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Autosomal recessive disorder
a1-antitrypsin inhibits proteases, esp neutrophil elastase, cathepsin G and proteinase 3
(released from neutrophils at inflammation sites)
Different mutations and combinations of mutations lead to different levels of disease due to
different levels of a1-antitrypsin being present
Pathogenesis:
o Defective migration of protein from ER to golgi apparatus  leads to apoptosis
o Series of events is triggered: autophagocytic response, mitochondrial dysfunction,
activation of pro-inflammatory NF-kB  hepatocyte damage
o But other environmental/genetic factors contribute to disease causation
Morphology:
o Round-oval cytoplasmic globular inclusions in hepatocytes (acidophilic)
 Mostly these surround the portal tracts (unknown why)
Clinical features: pulmonary emphysema (proteases not inhibited), liver disease (accumulation
in hepatocytes), cutaneous panniculitis, arterial aneurysm, bronchiectasis, Wegener’s
granulomatosis
Intrahepatic biliary tract disease
1. Secondary biliary cirrhosis
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Most often due to uncorrected obstruction of the extrahepatic biliary tree
o Adults: extrahepatic cholelithiasis, malignancy, strictures from previous surgeries
o Children: biliary atresia, CF, choledochal cysts, insufficient intrahepatic bile ducts
Morphology: yellow-green pigmented liver, icteric body fluids and tissues
o Cut surface is hard and has a finely granular appearance
o Histology: coarse fibrous septa
o Proliferation of smaller bile ductules
o Feathery degeneration and formation of bile lakes
2. Primary biliary cirrhosis
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Inflammatory autoimmune disorder of the intrahepatic biliary tree
Also see portal inflammation, scarring and eventual development of cirrhosis and liver failure
Mostly middle-aged females
Genetic and environmental factors are both thought to be important
Clinical signs: fatigue, pruritis, hepatomegaly, xanthelasmas, hyperpigmentation, inflammatory
arthropathy
Late features: signs and symptoms of chronic liver disease (eg. spider nevi), eventually cirrhosis
and portal hypertension complications
Serum alkaline phosphatase and serum cholesterol are almost always elevated at onset
Later hyperbilirubinaemia develops  shows incipient hepatic decompensation
Pathogenesis: unknown, potential mechanisms include
o Aberrant MHCII expression on bile duct epithelial cells
o Accumulation of autoreactive T cells around bile ducts
o Reaction of antimitochondrial antibodies to hepatocytes
Morphology:
o Small-duct biliary fibrosis and cirrhosis
o Infiltration of lymphocytes, macrophages, plasma cells ad occasional eosinophils
o Noncaseating granulomatous inflammation of interlobular bile ducts
o Eventually causes progressive secondary hepatic damage  portal tract scarring,
bridging fibrosis, cirrhosis
o Bile stasis slowly turns the liver green and a fine granularity of the capsule appears
o End-stage: indistinguishable from seconary biliary cirrhosis or other cirrhosis caused by
chronic hepatitis
3. Primary sclerosing cholangitis
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Inflammation and obliterative fibrosis of both the extrahepatic and intrahepatic biliary tree
Dilation of preserved segments
Possibly immunologically-mediated injury to bile ducts
Associated with IBD
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Morphology: fibrosing cholangitis of bile ducts with a lymphocytic infiltrate, progressive atrophy
of the bile duct epithelium and obliteration of the lumen
o Concentric periductal fibrosis around affected ducts  solid, cordlike fibrous scar
Clinical features: elevated serum alkaline phosphatase, fatigue, pruritis, jaundice
o Severe: chronic liver disease symptoms, weight loss, ascites, variceal bleeding,
encephalopathy, develop cholangiocarcinoma
4. Anomalies of the biliary trees
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Heterogenous group of lesions
o Von Meyenburg complexes
o Polycystic liver disease
o Congenital hepatic fibrosis
o Caroli disease
o Alagille syndrome
Circulatory disorders
1. Impaired blood flow to the liver
Manifestations: oesophageal varices, splenomegaly, intestinal congestion
Hepatic artery compromise
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Rarely causes infarcts due to dual blood supply
Thrombosis/compression of an intrahepatic branch of the hepatic artery can cause a localised
infarct (anaemic/pale tan or haemorrhagic)
Portal vein obstruction and thrombosis
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Abdominal pain + rupture of other oesophageal varices
Block is presinusoidal  therefore ascites is rare
Causes of extrahepatic portal vein obstruction include intra-abdominal sepsis, hypercoagulable
disorders, trauma, pancreatitis, pancreatic cancer, HCC invasion, cirrhosis
Intrahepatic portal vein obstruction is caused by thrombosis
Noncirrhotic portal fibrosis and idiopathic portal hypertension
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Pathogenesis unknown
Histology: variable involvement of the portal tracts, some inc in connective tissue deposition
and fibrosis  called hepatic sclerosis
2. Impaired blood flow through the liver
Causes: cirrhosis, sinusoid occlusion (due to sickle cell, DIC or metastasis)
Manifestations: ascites (cirrhosis), oesophageal varices (cirrhosis), hepatomegaly, raised
aminotransferases
Passive congestion and centrilobular necrosis
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Right-sided cardiac decompensation  passive congestion of liver
Left-sided cardiac failure/shock  hepatic hypoperfusion and hypoxia  centrilobular necrosis
Hypoperfusion + retrograde congestion  centrilobular haemorrhagic necrosis
Variegated haemorrhage and necrosis in the centrilobular regions (“nutmeg liver”)
Peliosis hepatis
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Primary sinusoidal dilation (rare condition)
Pathogenesis unknown, but includes focal apoptosis of hepatocytes/sinusoidal endothelial cells
and disruption of liver ECM
Associated with cancer, TB, AIDS, post-transplant immunodeficiency
Generally asymptomatic, but can have potentially fatal intra-abdominal haemorrhage or hepatic
failure
3. Hepatic venous outflow obstruction
Hepatic vein thrombosis and IVC thrombosis
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If obstruct 2+ main hepatic veins  liver enlargement, pain, ascites, Budd-Chiari syndrome
Morphology:
o Budd-Chiari syndrome: liver is swollen and red-purple; tense capsule
o Microscopic: hepatic parenchyma shows centrilobular congestion and necrosis
o Centrilobular fibrosis develops in a slowly-growing thrombus
High mortality if untreated
Sinusoidal obstruction syndrome (veno-occlusive disease)
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Primarily occurs following allogeneic BM transplant
Due to toxic injury to the sinusoidal endothelium
Tender hepatomegaly, ascites, weight gain, jaundice
Morphology: obliteration of hepatic vein radicles by subendothelial swelling and finely
reticulated collagen
o Acute: striking centrilobular congestion + hepatocellular necrosis and accumulation of
haemosiderin-laden macrophages
o Then obliteration of the lumen (use connective tissue stain)
o Chronic: dense perivenular fibrosis radiating into the parenchyma + total obliteration of
the venule; haemosiderin deposition in the scar tissue; minimal congestion
Nodules and tumours
1. Nodular hyperplasias
Focal nodular hyperplasia
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Young to middle-aged adults
Well demarcated, but poorly encapsulated nodule
Spontaneous mass lesion in an otherwise healthy liver
Lesion: lighter, sometimes yellow  central grey-white are, depressed stellate scar (fibrous
septa radiate to the periphery)
Central scar contains large vessels with fibromuscular hyperplasia
Nodular regenerative hyperplasia
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Entire liver has roughly spherical nodules, but no fibrosis
Microscopic: plump hepatocytes surrounded by rims of atrophic hepatocytes
Altered hepatocellular architecture seen with reticulin staining
Can lead to portal hypertension
2. Benign neoplasms
Cavernous haemangiomas
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Small, discrete, red-blue, soft nodules directly beneath the capsule
Hepatic adenoma
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Mostly in young women who have used OCP  stopping use can lead to tumour regression
Clinical significance
o Can be mistaken for HCC
o Subcapsular adenomas can rupture (esp if pregnant)
o Can transform into carcinomas (rare)
Pathogenesis
o Unknown, but involves hormonal stimulation
o Transcription factor mutations
o Morphology: pale, yellow-tan, + bile stained
 Often beneath capsule
 <30cm diameter
 Well demarcated, but not always encapsulated
 Usually solitary, but can be multiple lesions
 Portal tracts are absent, but there are prominent solitary arterial vessels and
draining veins
3. Malignant tumours
Hepatoblastoma
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Young children, fatal if not treated, very rare
Anatomic variants: epithelial type; mixed epithelial and mesenchymal type
Chromosomal abnormalities are common
Tx: chemotherapy, complete surgical resection
Hepatocellular carcinoma
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3rd most frequent cause of cancer deaths
82% cases in developing countries with chronic HBV infections
Males > females
Aetiology:
o Chronic viral infection (HBV, HCV)
o Chronic alcoholism
o Non-alcoholic steatohepatitis
o Food contaminants (primarily aflatoxins)
o Tyrosinaemia, glycogen storage disease, hereditary haemochromatosis, NAFLD, a1antitrypsin deficiency
Pathogenesis:
o Exact pathogenesis is unknown
o Repeated cycles of cell death and regeneration (eg. in chronic hepatitis)  mutations 
impaired DNA repair mechanisms  transformed hepatocytes
o KRAS and p53 might be mutated
o Viral integration precedes or accompanies a transforming event (potential protooncogene activation, or possibly a viral protein may be a transcriptional activator)
Morphology:
o Gross: unifocal large mass; multifocal, widely distributed nodules of various size or;
diffusely infiltrative cancer
o Gross: liver enlargement, HCC is paler (+ green)
o Strong propensity for invasion of vascular structures
o Intrahepatic metastases, + masses of tumour invade the portal vein or IVC potentially
into the heart
o Can have satellite nodules spreading
o LNs involved first: perihilar, peripancreatic, para-aortic (but usually spread by BV)
o Can be highly differentiated or anaplastic, undifferentiated
Clinical features
o Rarely characteristic, often masked by underlying cirrhosis/hepatitis
o Ill-defined upper abdominal pain, malaise, fatigue, weight loss, awareness of abdominal
mass/fullness
o Laboratory (rarely conclusive): elevated serum a-fetoprotein
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Death from: cachexia; GI or oesophageal variceal bleeding; liver failure + hepatic coma;
rupture of the tumour with fatal haemorrhage
Cholangiocarcinoma
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RF: primary sclerosing cholangitis, congenital fibropolycystic disease of the biliary system, HCV
infection, Thorotrast exposure
80-90% extrahepatic (eg. perihilar)
Morphology: extrahepatic CCA
o Generally small at diagnosis  firm, grey nodules within bile duct wall
o Some are diffusely infiltrative lesions, other papillary, polypoid lesions
o Mostly adenocarcinomas (may/may not secrete mucin)
Morphology: intrahepatic CCA
o Noncirrhotic liver, + track along intrahepatic portal tract system
o Or a massive tumour nodule may develop
o Vascular invasion and propagation via lymphatics lead to intrahepatic metastasis
o Microscopy: resembles other adenocarcinomas (glandular/tubular structures lined with
cuboidal – low columnar epithelial cells)
3 types of mixed HCC and CCA
o Separate tumour masses of HCC and CCA
o Collision tumours (identifiable interface)
o Tumours with intimate mixing at microscopic level (common bipotential precursor cell)
Pathogenesis:
o IL-6 overexpression  AKT activation, MCL-1 activation  anti-apoptotic
o Also KRAS and p53 involvement
o Many other signalling pathways also
4. Metastatic tumours
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Far more common than primary malignancy
Most commonly from: colon, breast, lung, pancreas
But can be from any cancer anywhere in the body
Multiple nodular metastases, hepatomegaly, can replace <80% hepatic parenchyma
If massive destruction: jaundice and elevated liver enzymes