Please enable JavaScript.
Coggle requires JavaScript to display documents.
Liver & Biliary Tract Pathology (General Features of Hepatic Disease…
Liver & Biliary Tract Pathology
General Features of Hepatic Disease
Hepatic Failure
Classifications:
Acute Liver Failure
Acute liver illness asc with encephalopathy within 6 months after initial diagnosis
If encephalopathy sets in within 2 weeks of onset of jaundice, known as fulminant liver failure
Caused by drugs, HAV, HBV, toxins and chemicals
Chronic liver disease
Most common route to liver failure
Ends in eventual cirrhosis
Hepatic dysfunction without overt necrosis
Hepatocytes remain viable but are unable to perform normal metabolic functions
Caused by tetracycline toxicity and acute fatty liver of pregnancy
Pathological Effects:
Impaired
bilirubin
metabolism
Leads to jaundice
Impaired
protein
synthesis
Leads to hypoalbuminemia --> peripheral oedema and ascites
Impaired
clotting factor
synthesis
Leads to coagulopathy with increasing bleeding tendencies
Impaired
hormone inactivation
Leads to hyperestrinism:
Spider naevi
Palmar erythema
Gynaecomastia
Impaired
detoxification
Leads to hyperammonemia - which can cause hepatic encephalopathy
Fetor hepaticus (characteristic musty body odour due to mercaptans formed by GI bacteria action on methionine being shunted into systemic circulation)
Complications:
Hepatic encephalopathy
Disorder of neurotransmission in CNS and neuromuscular system
Due to elevated blood levels of ammonia which impairs neuronal function
Neurological signs:
Rigidity
Hyperreflexia
Asterixis (liver flap)
Hepatorenal syndrome
Appearance of renal failure in individuals with serve
chronic liver disease in whom there are no intrinsic
morphologic or functional causes for renal failure
Splanchnic vasodilation due to portal HTN --> RAAS activation --> afferent renal bv constriction, reducing perfusion
Hepatopulmonary syndrome
Clinical triad: chronic liver disease, hypoxemia, intrapulmonary vascular dilation
Due to enhanced nitric oxide production by the lung
Cirrhosis
End stage of chronic liver disease
3 defining morphologic characteristics:
Bridging fibrous septa
Parenchymal nodules
Disruption of the architecture of the entire liver
Causes of Cirrhosis:
Alcoholic liver disease
Chronic viral hepatitis
Chronic HBV infection
Chronic HCV infection
Intrahepatic biliary cirrhosis
Primary biliary cirrhosis
Secondary biliary cirrhosis
Primary sclerosing cholangitis
Metabolic liver diseases:
Hemochromatosis (pigment cirrhosis)
Excessive iron absorption and deposition
Wilson disease
Copper accumulation in liver
alpha 1 - antitrypsin deficiency
Neutrophil elastase not inhibited - breaks down elastin in lungs and liver
NAFLD
Pathogenesis:
Chronic liver disease with chronic inflammation results in progressive fibrosis of the liver:
Major factor: hepatic
stellate cells
(aka Ito cells found in Space of Disse, normally stores Vit A)
Under stress, Ito cells get converted to myoepitheial cells which lay down interstitial collagen in space of Disse
This creates
fibrous septal tracts
Fibrous septal tracts impair solute exchange between hepatocytes and plasma
Deposition of collagen in Space of Disse causes "capillarization" of hepatic sinusoids due to loss of fenestrations
New vascular channels develop within the fibrous septa which further shunts blood away from the liver parenchyma
Hepatocyte death and regeneration within the confines of the bridging fibrous septa
Forms
parenchymal nodules
without the normal hepatic lobular architecture
On the whole, this process occurs diffusely throughout the liver -->
architectural disruption of liver
Morphology
Gross:
Enlarged in early stage, shrunken in late stage
Nodular surface texture
Variety of colours may be seen
Yellow in fatty change
Grey in viral hepatitis
Green in jaundice
Brown in hemochromatosis)
Histology:
Bridging fibrous septa
Parenchymal nodules comprising hepatocytes
Micronodular (<3mm): alcoholic cirrhosis
Macronodular (>3mm): viral hepatitis cirrhosis
Irregular nodules: biliary cirrhosis
Inflammatory infiltrate
Ductular proliferation within fibrous septa
Cholestasis
Piecemeal necrosis/interface hepatitis (necrosis of the limiting plate of the first row of hepatocytes)
Other specific features of specific etiologies:
Mallory bodies
- reticular eosinophilic depositions in liver cells due to intermediate filament damage
Alcoholic cirrhosis, Wilson disease
Groundglass hepatocytes
- due to intracellular accumulation of HBsAg
HBV cirrhosis
Hemosiderin
(use Perl's stain or Prussian blue)
Pigment cirrhosis
Aggregated copper within lysosomes principally in the periphery of the nodule
(use rhodamine stain)
Wilson disease
alpha-1 anti-trypsin globules in cytoplasm of hepatocytes
(PAS positive, diastase resistant):
alpha-1 anti-trypsin deficiency cirrhosis
Pathological Effects and Complications:
Progressive hepatic failure
Development of
portal HTN
Hepatocellular carcinoma
Portal HTN
Raised BP within the portal venous system
Causes:
Prehepatic
causes
Obstructive thrombosis of portal vein
Massive splenomegaly with consequent increased splenic vein blood flow
Intrahepatic
causes
Cirrhosis
(causes most cases of portal HTN)
Schistosomiasis
Massive fatty change
Caroli disease
Sarcoidosis
Posthepatic
causes
Severe R heart failure
Constrictive pericarditis
Hepatic vein outflow obstruction (Budd Chiari syndrome)
Pathogenesis of Portal HTN in Cirrhosis
Increase in resistance to portal blood flow at level of hepatic sinusoids
Parenchymal nodules compress sinuosids
Contraction of vascular smooth muscle cells and myofibroblasts
Hepatic artery - portal vein shunt formation
Anastomoses form between branches of the hepatic artery & portal vein within the fibrous septa
In turn imposes high arterial pressures of hepatic artery on low pressure portal venous system
Increased portal blood flow (hyperdynamic circulation)
Reduced clearance of bacterial DNA absorbed from gut & carried to liver (due to impaired solute exchange between hepatocytes & plasma in cirrhosis)
Stimulates increased nitric oxide production
In turn causes splanchnic arterial vasodilation
Pathological Effects and Complications
1. Ascites
Increased fluid shift into space of Disse from intravascular compartment due to increased sinusoidal hydrostatic pressure in portal HTN
Accompanied by decreased plasma oncotic pressure due to hypoalbuminemia and water/sodium retention
Increased fluid shift leading to increased lymphatic drainage from the liver overwhelms thoracic duct capacity --> percolation of lymph into peritoneal cavity
2. Formation of portosystemic shunts
Increased portal venous pressures causes dilation of anastomotic channels, allowing collateral flow of portal blood into systemic veins
Periumbilical veins - Supf abdominal veins (when dilated --> caput medusae)
Gastric veins - Lower oesophageal veins (when dilated --> oesophageal varices)
Rupture of esophageal varices can result in potentially fatal hematemesis
Sup rectal veins - Inf rectal veins (when dilated --> haemorrhoids)
Portosystemic shunting exacerbates problems associated with shunting of blood through liver (e.g. hyperammonemia)
3. Congestive Splenomegaly
Splenomegaly secondary to longstanding portal HTN
Results in pathological effects of hypersplenism (anaemia, thrombocytopenia, leukocytopenia)
4. Hepatic Encephalopathy
Due to hyperammonemia exacerbated by portosystemic shunting
Jaundice & Cholestasis
Jaundice: Yellow pigmentation of skin due to hyperbilirubinemia
Cholestasis: Accumulation of bile pigment within hepatic parenchyma
Hepatic (hepatocellular) causes:
Widespread hepatocellular disease (hepatitis, cirrhosis)
Physiologic jaundice of the newborn
:
Due to immaturity of hepatic conjugation enzymes before 2nd week of life
Gilbert syndrome
:
AR inheritance
Mildly decreased glucuronyl transferase activity (30% of normal)
Causes mild fluctuating hyperbilirubinemia
Crigler-Najjar syndrome Type I
:
AR inheritance
Complete absence of glucuronyl transferase
Invariably fatal by 18 months without liver transplantation
Crigler-Najjar syndrome Type II
:
AD inheritance
Greatly decreased glucuronyl transferase activity (can only form monoglucuronidated bilirubin)
Causes very yellow skin
Dubin-Johnson syndrome
:
AR inheritance
Absence of MDR2 transporter resulting in failure to transport conjugated bilirubin out of hepatocytes into bile canaliculi
Generally innocuous
Rotor syndrome
:
AR inheritance
Multiple defects in uptake and excretion of bilirubin into and out of hepatocytes
Generally innocuous
Clinical Features of Hepatic Jaundice:
Jaundice:
Conjugated hyperbilirubinemia
Orange tint
Stools: normal colour
Urine:
tea colour
Anorexia
Hepatic tenderness
Spleen is normal size or enlarged
Liver function test:
ALT & AST: raised
ALT > AST: Viral (ALT in cytoplasm)
AST > ALT: Toxins (AST in mitochondria)
Alkaline phosphatase & GGT: raised (in cholestatic phase)
Liver proteins: reduced (in chronic liver failure)
Prehepatic (hemolytic) causes:
Haemolytic anemia
Resorption of blood from large internal haemorrhages
Ineffective erythropoiesis
Clinical Features of Prehepatic Jaundice:
Jaundice
Unconjugated hyperbilirubinemia
Lemon yellow
Stools:
dark
colour (increased stercobilin)
Urine: normal colour (unconjugated bilirubin cannot be filtered into urine)
Pruritis absent (no bile accumulation)
Anemia with reticulocytosis
Splenomegaly
Liver function test:
ALT & AST: normal
Alkaline phosphatase & GGT: normal
Liver proteins: normal
Post hepatic (obstructive) causes:
Gallstones
Carcinomas of head of pancreas, bile duct carcinoma, tumours of ampulla of Vater
Extrahepatic biliary atresia
Clinical Features of Posthepatic Jaundice:
Jaundice:
Conjugated hyperbilirubinemia
Greenish tinge
Stools:
pale
(no bile pigments)
Urine:
dark
(bilirubinemia, no urobilin)
Pruritis & scratch marks
(bile accumulation)
Enlarged gallbladder
Liver function test:
ALT & AST: mildly elevated
Alkaline phosphatase & GGT: raised
Liver proteins: normal
Infections
Non-Hepatitis Viruses
EBV - During acute phase of infectious mononucleosis
In children and IC:
CMV (newborns)
Rubella
Adenovirus
Enterovirus
Bacterial, Fungal, Parasitic, Helminthic:
Pyogenic infections:
Pyemic (haematogenous)
Cholangitic (asc cholangitis)
Direct spread
Tuberculosis
Amoebic abscess
Hepatitis Viruses
HAV
Causes acute and fulminant hepatitis
Faecal-oral transmission (shellfish, water)
Short incubation period (2-6 weeks)
Diagnosis:
IgM-HAV
HBV
Causes acute, fulminant and chronic hepatitis
Minority of HBV infected progress to chronic hepatitis
Inactive (healthy) carrier has:
HBsAg and anti-Hbe
No HBeAg
Serum HBV DNA low/undetectable
No inflammation
Blood and vertical (usu perinatal) transmission
Long incubation period (4-26 weeks)
Can cause acute glomerulonephritis and vasculitis (specifically polyarteritis nodosa) in chronic HBV infection due to circulating immune complexes
Diagnosis:
anti-HBs, HBV DNA
HCV
Causes acute (typically subclinical) and chronic hepatitis
Majority of HCV infected progress to chronic hepatitis
Blood transmission
Long incubation period (42-90 days)
Inherently unstable due to poor fidelity of bacterial RNA polymerase --> results in ineffective immunity conferred by IgG produced after an active infection
Diagnosis:
HCV RNA
HDV
Defective RNA virus that requires HBV for its replication
Co-infection
Simultaneous with HBV - clinically indistinguishable from acute HBV infection
Super infection
HDV infecting HBV carrier or HBV-chronically infected patient
Diagnosis:
anti-delta IgM
HEV
Causes acute hepatitis
Faecal-oral transmission(water-borne, zoonotic)
Incubation period (35-40 days)
Characteristically high fatality rate among HEV-infected pregnant women
Diagnosis:
anti-HEV
Features of Acute Hepatitis:
Morphology:
Diffuse hepatocellular injury and lobular disarray
Focal necrosis
Councilman bodies (round, red lobules which are apoptotic bodies)
Cholestasis
Inflammatory infiltrate in portal tract which may spillover into adjacent parenchyma causing apoptosis of periportal hepatocytes (interface hepatitis)
Kupffer cell hypertrophy and hyperplasia, laden with lipofuscin due to phagocytosis of debris
Hepatocyte regeneration
Bridging necrosis (confluent necrosis of hepatocytes) and piecemeal necrosis
Groundless hepatocytes
Outcomes of acute viral infection:
Hyper immune response:
Fulminant hepatitis (seen mainly in HAV and HBV)
Normal immune response:
Acute hepatitis (may be symptomatic or asymptomatic)
Less adequate immune response:
Chronic hepatitis (seen only in HBV and HCV)
Totally inadequate immune response:
Asymptomatic carrier status (seen only in HBV and HCV)
Features of Chronic Hepatitis
Symptomatic, biochemical or serologic evidence of ongoing hepatic disease for more than 6 months with histologically documented inflammation & necrosis
Morphology:
Hepatocyte injury & necrosis
Portal inflammation (continued interface hepatitis, bridging inflammation & necrosis)
Fibrosis (periportal & bridging fibrous septa)
Causes:
Chronic viral infection (HBV, HCV, HDV)
Alcoholic liver disease
Metabolic liver disease
Autoimmune hepatitis
Drug-induced hepatitis
Grading of Chronic Hepatitis:
A measure of the severity of the necroinflammatory process (gauged by the degree of interface activity)
May not correlated well with clinical & biochemical
Drug & Toxin-Induced Liver Disease
Drug-Induced Liver Disease
Liver is the main drug metabolizing and detoxifying organ in the body
Mild to serious to fatal reactions
A diagnosis of drug/toxin-induced liver injury (DILI) may be made on the basis of:
A temporal association of liver damage with drug/toxin exposure
Recovery (usually) upon removal of the inciting agent
Exclusion of other potential cause
Exposure to a toxin or therapeutic agent should always be included in the differential diagnosis of any form of liver disease
Drugs, medicines, herbal remedies, dietary supplements, topical applications (eg. Ointments, perfumes, shampoos), env exposures (eg. Cleaning solvents, pesticides, fertilizers)
Most drugs or toxins affecting the liver may be classified as:
Predictable hepatotoxins, acting in a dose-dependent manner and occuring in most individuals
Unpredictable or idiosyncratic hepatotoxins which happen in rare individuals and which are often independent or dose dependent
Hepatotoxins may cause harm:
From direct cell toxicity
Through hepatic conversion of a xenobiotic to an active toxin
By immune mechanisms, such as by the drug or a metabolite acting as a hapten to convert a cellular protein into an immunogen
Most common hepatotoxin causing acute liver failure is
acetaminophen
Alcoholic Liver Disease
3 distinct, albeit overlapping forms
Hepatic Steatosis (Fatty Liver)
Pathogenesis:
Generation of excess NADH by alcohol dehydrogenase and acetaldehyde dehydrogenase
Excess NADH shunts normal substrates away from catabolism and towards lipid biosynthesis
Also, assembly and secretion of lipoproteins are impaired, leading to intracellular lipid accumulation
Morphology:
Microvesicular (short-term) or macro vesicular (chronic intake) lipid globules within hepatocytes
Liver appears
large, soft and yellow
Fatty change is completely
reversible
with abstention from alcohol
Centrilobular fibrosis develops with continued alcohol intake
Alcoholic Hepatitis
Pathogenesis:
Acetaldehyde-induced lipid peroxidation
Acetaldehyde-protein adduct formation
Increased production of reactive oxygen species
Impaired methionine metabolism which decreases intracellular glutathione levels, hence reducing
hepatic resistance towards oxidative injury
Morphology:
Fatty change
in centrilobular zone of hepatocytes (reversible)
Hepatocyte swelling
(ballooning degeneration) and necrosis
Mallory bodies
Neutrophilic reaction
Pericellular/perisinusoidal fibrosis
Cirrhosis
Alcoholic Cirrhosis
Pathogenesis:
End stage of prolonged alcoholic hepatitis
Morphology:
Micronodular parenchymal nodules (<3mm)
Fatty change (minimally evident in late stages)
Mallory bodies
Metabolic Liver Diseases
Hemochromatosis
Excessive accumulation of iron within the body (normal = 2-6g)
Pathogenesis:
Hereditary
hemochromatosis
Mutations of genes encoding proteins involved in iron homeostasis
HFE, transferring receptor 2, Hepcidin, Hemojuvelin
Acquired
hemochromatosis (aka hemosiderosis)
Parenteral iron overload (transfusions, long-term hemodialysis)
Ineffective erythropoiesis (thalessemia, myelodysplastic syndromes)
Increased oral iron intake (Bantu siderosis)
Pathological effects and complications:
Liver deposition:
Pigment cirrhosis
Pancreas deposition:
Diabetes mellitus (due to islet destruction)
Heart deposition:
Arrhythmias
Skin deposition:
Skin pigmentation
Joints deposition:
Atypical arthritis
Endocrine glands deposition:
Hypogonadism (amenorrhea, impotence, libido loss)
Wilson Disease
Genetic disease causing accumulation of copper within the body
Pathogenesis:
AR disorder caused by a mutation of the ATP7B gene:
Encodes a copper transporting ATPase on hepatocyte canalicular membrane
Results in accumulation of cooper due to:
Impaired copper excretion into bile and faeces
Impaired incorporation of copper into ceruloplasmin
(meant for copper transport in blood)
Pathological effects and complications:
Accumulation in liver:
Cirrhosis asc with Wilson disease
Accumulation in basal ganglia of brain:
Chorea
Mild behavioural changes
Frank psychosis
Accumulation in eye:
Kayer-fleischer rings
Biochemical Diagnosis:
Decreased serum ceruloplasmin
Increased hepatic copper content
Increased urinary copper excretion
Serum copper levels are of no value
Treatment:
Long term copper chelation therapy with D-penicillamine
Liver transplant
Alpha-1 Antitrypsin Deficiency
Pathogenesis:
AR disorder caused by mutation of alpha-1 antitrypsin gene (codes for antitrypsin, an anti-protease)
Pathological effects and Complications:
Liver - Cirrhosis asc with alpha-1 antitrypsin deficiency
Lung - Emphysema
NAFLD
Leading cause of chronic liver disease in adults and children
Association with metabolic syndrome which comprises
obesity, type 2 diabetes, HTN and hyperlipidemia
Pathogenesis:
There are several mechanisms by which excess triglycerides are acquired and accumulate in hepatocytes
These
lead to liver injury via insulin resistance and an excess of free FAs in hepatocytes
, resulting in
oxidative stress and lipotoxicity
that promote the activation of intracellular stress kinases and apoptosis or necroapoptosis (NASH)
The damaged hepatocytes directly trigger inflammation and fibrogenesis, but can also lead to the emergence of fibrogenic progenitor cells
Visceral adipose tissue dysfunction in obesity and insulin resistance results in aberrant cytokine expression, leading to inflammation that involves mainly macrophages and humoral factors, such as adipokines and cytokines
The course of NAFLD is highly variable, only a minority of patients (2-3%) progress to end-stage liver disease
NAFLD/NASH has been reported as a cause of hepatocellular carcinoma
Clinical Features:
Asymptomatic
Fatigue or R sided abdominal discomfort
Serum AST and ALT elevation
Treatment:
Weight loss and exercise
Management of metabolic syndrome component
Intrahepatic Biliary Tract Diseases
Primary Biliary Cirrhosis
Autoimmune disease mainly affecting the intrahepatic bile ducts. Characterised by a non-suppurative inflammatory destruction of medium-sized intrahepatic bile ducts
Pathological effects and complications:
Progressive inflammation, scarring and eventual cirrhosis
Liver failure
Portal HTN and variceal bleeding
Increased risk of HCC
Morphology:
Periportal fibrosis
Mononuclear infiltrate
Lymphoid follicle
Non-Caveating granuloma
Non-suppurative destructive cholangitis
Secondary Biliary Cirrhosis
Disorder of intrahepatic bile ducts due to uncorrected extra hepatic bile duct obstruction
Causes:
In children:
Biliary atresia
Cystic fibrosis
Choledochal cysts
In adults:
Gallstones
Carcinoma bile duct, tumours of pancreas head or ampulla of Vater
Morphology:
Periportal fibrosis
Prominent cholestasis (bile lakes)
Bile duct proliferation
Neutrophilic infiltrate
Intraduct neutrophils
Primary Sclerosing Cholangitis
Inflammation & obliterative fibrosis of intrahepatic & extrahepatic bile ducts, with dilation of preserved segments; produces a characteristic ‘beading’ of contract medium in radiographs of biliary tree
Associations:
Inflammatory bowel disease
Pathological effects and complications:
Biliary cirrhosis
Increased risk of cholangiocarcinoma
Symptoms of chronic liver disease (weight loss, ascites, encephalopathy, variceal bleeding)
Morphology:
Lymphocytic infiltrate
Progressive atrophy of bile duct epithelium
Obliteration of bile duct lumen
Concentric periductal fibrosis (onion-skin appearance) following obliteration of lumen
Circulatory Disorders
Impaired blood flow into liver
Manifestations:
Splenomegaly
Oesophageal varices
Intestinal congestion
Hepatic Artery Obstruction:
Causes:
Hepatic artery thrombosis, thromboembolism
Polyarteritis nodosa
Malignancy
Portal vein obstruction:
Causes:
Malignancy
Peritoneal sepsis
Pancreatitis (initiates splenic vein thrombosis which can propagate into the portal vein)
Hypercoagulable states
Cirrhosis
Impaired blood flow through liver
Manifestations:
Ascites
Oesophageal varices
Hepatomegaly
Elevated aminotransferases
Passive Congestion
Causes:
CHF
Morphology:
Liver slightly enlarged, tense and cyanotic
Nutmeg liver appearance (variegated, mottled)
Centrilobular fibrosis
Centrilobular hemorrhagic necrosis
Peliosis Hepatitis
Primary sinusoidal dilations forming blood-filled cystic spaces within the liver
Associations:
Bartonella spp., Tuberculosis, AIDS
Cancer
Post-transplant immunodeficiency
Hepatic venous outflow obstruction
Hepatic Vein Obstruction (Budd-Chiari Syndrome)
Only becomes clinically apparent when 2 or more of the 3
hepatic veins are obstructed
Causes:
Hepatic vein thrombosis
Primary myeloproliferative disorders
Inherited disorders of coagulation
Oral contraceptives, pregnancy
Tumour invasion of hepatic vein (hepatocellular carcinoma, renal cell carcinoma)
Sinusoidal Obstruction Syndrome (Veno-Occlusive Disease)
Damage to sinusoidal endothelium with resultant cellular debris embolizing downstream and occluding terminal hepatic veins
Causes:
Bush-tea (pyrrolizidine alkaloid)
Allogeneic bone marrow transplantation
Chemotherapy (gemtuzumad, ozagmamicin, actinomycin D, cyclophosphamide)
Congenital Abnormalities
Extrahepatic Biliary Atresia
Complete obstruction of the lumen of the extrahepatic biliary tree within the first 3 months of life
2 main modes of pathogenesis:
Fetal form:
Due to aberrant intrauterine development of the extra hepatic biliary tree
Perinatal form:
Due to obstruction of normally developed biliary tree following birth (eg. due to viral infections)
3 main clinical types:
Type I: limited to common bile duct
Type II: limited to the hepatic bile ducts
Type III: includes obstruction of bile ducts at/above
the level of the porta hepatis
Morphology:
Severe cholestasis
Marked bile ductular proliferation
Inflammatory cellular infiltration (neutrophilic)
Biliary fibrosis
Biliary cirrhosis
Obstructive jaundice with pale stools
Treatment:
Hepatic porto-enterostomy (Kasai procedure –
involves bypassing of segment of atresia by creating
an anastomosis): for types I & II
Liver transplantation: for type III
Polycystic Liver Disease
Multiple diffuse cystic lesions in the liver
Various sizes
Numbers range from a scattered few to hundreds
Non-communicating in nature (do not communicate
with biliary tract, less risk of malignant
transformation)
Associations:
Cystic lesions in kidney & pancreas
Strongly associated with AD form of polycystic
kidney disease
Clinical features:
Typically asymptomatic
Disorders of the Gallbladder and Extrahepatic Bile Ducts
Cholelithiasis
Epidemiology & Associations:
Fat
Asc with metabolic syndrome
Female
Forty
Fertile
Estrogenic influence (incl pregnancy and contraceptive use, due to increase in uptake and biosynthesis of cholesterol in the liver --> secondary increase in biliary cholesterol syndrome
Types of Stones:
1. Pure cholesterol stone
Yellow, finely granular, hard
Radiolucent
2. Pure pigment stone - calcium bilirubinate (unconjugated)
Black (sterile - mostly radiopaque)
Brown (infected - mostly radiolucent), friable
Risk factors:
Haemolytic anemias
Increases biliary bilirubin excretion
Biliary tract infection
Release of microbial beta-glucoronidases prematurely --> deconjugates conjugated bilirubin
Ascaris lumbricoides, liver flukes
3. Pure calcium carbonate stone
4. Mixed stones, combined stones
Pathogenesis of Cholesterol Stones
Supersaturation
of cholesterol
Cholesterol conc > solubilisation capacity of bile salts and lecithin
May be due to excessive biliary cholesterol or insufficient bile salt formation
Hypomotility
of the gallbladder
Promotes cholesterol nucleation
Accelerated
cholesterol crystal nucleation
Hypersecretion
of mucus in gallbladder trapping
Complications
1. Cholecystitis
Empyema (gallbladder converted to a bag of pus)
Hydrops of gallbladder (chronically obstructed atrophic gallbladder)
2. Common bile duct obstruction
, leading to:
Obstructive jaundice
Ascending cholangitis
Secondary biliary cirrhosis
3. Cholecystointestinal fistula formation
As inflammation of gallbladder can result in formation of adhesions with intestine --> converted into fistula over time
Large stones can directly enter the gut, causing intestinal obstruction
4. Bouveret syndrome (gallstone ileus)
Direct erosion of a large gallstone through gallbladder into GIT
5. Carcinoma gallbladder
Empyema (gallbladder converted to a bag of pus)
Cholecystitis
Inflammation of the gallbladder, may be acute, chronic, acute-on-chronic
Acute Cholecystitis:
Gross:
Enlarged and tense
Fibrinosuppurative serosal surface
Histology:
Acute inflammatory infiltrate
Pathogenesis:
1. Acute calculous cholecystitis
Due to obstruction by gallstone
Mucosal phopholipases hydrolyse lecithins to lysolecithins, which disrupt normally protective mucus layer
This exposes the mucosa to direct detergent action of bile salts, resulting in inflammation
Gall bladder dysmobility then develops, leading to distension & increase in intraluminal pressure
Blood flow is then compromised, leading to ischemic damage to the gallbladder
Bacterial infection typically imposed upon initial mechanical & chemical factors
2. Acute calculus cholecystitis
No gallstones involved in pathogenesis
Causes:
Sepsis with hypotension, immunosuppression, major trauma and burns, diabetes mellitus, Salmonella Typhi infection
Pathological effects and complications:
Pericholecystic and sub diaphragmatic abscess
Peritonitis
Ascending cholangitis and liver abscess
Septicaemia
Chronic Cholecystitis:
Gross:
Thickened, contracted wall
Asc with obstructive calculi
Histology:
Chronic inflammatory infiltrate
Muscular hypertrophy
Rokintansky-Aschoff sinuses
Dystrophic calcification - gives rise to a porcelain gallbladder
Neoplasms
Liver is the most common site of metastatic cancers from colon, lung and breast etc
Main primary malignancies:
Hepatocellular carcinoma (HCC) (90%)
Cholangiocarcinoma (CC) (10%)
Epithelial
Liver Cell (Hepatocyte)
Malignant
1. Hepatocellular Carcinoma
Natural Course of HCC:
Progressive enlargement of mass till it disrupts liver function or distant metastases
Survival < 2 years
Causes of death:
Cachexia
GIT or esophageal variceal bleeding
Liver failure with hepatic coma
Rupture of tumor with fatal hemorrhage
Screening and surveillance:
Ultrasonography and serum AFP
CT and MRI with vascular/contrast studies (tumors < 2cm)
Management:
Surgical resection
Locoregional ablation: Transarterial chemoembolization (TACE) or radiofrequency ablation (RFA)
Prognostic factors:
Stage, Grade
Encapsulation
Number and size of tumours
Presence of cirrhosis (worse)
Intravascular spread
Serum AFP
Clinical Features:
Symptoms:
Asymptomatic
Upper abdominal pain, malaise, fatigue, weight loss
Hepatomegaly
Jaundice, variceal bleeding
Haematogenous spread
- Preference for invasion of vascular structures
Portal vein obstruction
Hepatic vein obstruction (Budd-Chiari syndrome)
Tumour marker: alpha-fetoprotein
Gross:
May appear as
Unifocal mass (usually large)
Multifocal widely distributed noodles (typically against a background of cirrhosis)
Diffuse infiltrative cancer
Variegated in cut section
Yellow background, grey necrosis, red haemorrhage, green bile
Histology:
Well, moderately to poorly differentiated
Trabeculae of hepatocytes separated by sinusoids
Neoplastic hepatocytes have eosinophilic cytoplasm, display
pleomorphism
, central round nucleus with distinct nucleolus
Bile production
(HCC is the only tumours that produces bile)
Epidemiology:
5% of all cancers
Global distribution of cases coincides with distribution of HBV endemicity
Etiologies and associations:
Cirrhosis
(alcohol)
HBV, HCV
NAFLD asc with metabolic syndrome
Metabolic disease (hereditary hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency)
Activation of beta-catenin and p53 inactivation are two most common early mutational events
Aflatoxins
Produced by fungus Aspergillus flavus
Gives characteristic p53 mutation
2. Hepatoblastoma
Epidemiology and Associations:
Rare
Occurs almost exclusively in infants
Not associated with cirrhosis
Variety of mutations:
APC gene (FAP)
Beta-catenin
Chromosomal abnormalities
Morphology:
Primitive looking neoplastic hepatocytes
Presence of non-hepatic tissue types (eg. osteoid)
2 histological variants:
Epithelial type - fatal or embryonal cells
Mixed epithelial and mesenchymal type - primitive mesenchyme, osteoid, cartilage, striated muscle
Clinical Features:
Tumour marker: alpha-fetoprotein
Prognostic factors:
Stage
Histologic subtypes (fetal type better prognosis, anaplastic and macrotrabecular types worse prognosis)
Generally better prognosis than HCC
Usually fatal if untreated. 5 year survival with therapy = 80%
Benign
1. Hepatocellular Adenoma
Epidemiology and Associations:
Occurs exclusively in women of childbearing age - strongly asc with
female hormones
(incl contraceptives)
Pathological Effects and Complications:
Abdominal discomfort
Intraperitoneal haemorrhage (those in sub capsular regions)
Risk of malignant transformation
Gross:
Solitary, well-defined lesion
2-15cm in diameter
Yellowish
Histology:
Well differentiated trabecular of liver cords separated by sinusoids
Prominent vessels distributed through the tumours substance
Absence of normal portal tracts
2. Focal Nodular Hyperplasia
Benign tumor-like condition of liver occuring in normal liver following a
localized ischemic event
Pale lobulated mass with central scar
Lobules of hyper plastic hepatocytes with central fibrous scar containing mishapen thick-walled arteries, absent bile ducts, and ductular reaction
Bile Duct
Benign
Bile duct hamartoma
Bile duct adenoma
Malignant
1. Cholangiocarcinoma
Primary malignant tumour of the biliary tree (intra- and extra hepatic bile ducts)
< 10% of primary liver cancers
Etiologies and associations:
Liver fluke infestation
(Opisthorchis and Clonorchis species - found in small fish in paddy fields)
Northeastern Thailand, Laos and Cambodia
Hepatolithiasis
Primary sclerosing cholangitis
Fibropolycystic liver disease
HBV, HCV and NAFLD
Pathogenesis:
All risk factors cause chronic inflammation and cholestasis which promote occurrence of somatic mutations or epigenetic alterations in cholangiocytes
Precursor lesion – Biliary Intraepithelial Neoplasia (BIN)
Intra- and extra hepatic Cholangiocarcinomas
50-60% of all CC are perihilar or Klatskin tumors
20-30% are in CBD
10% are intrahepatic CC
Adenocarcinomas, well to poorly differentiated
Lymphovascular and perineural spread
Porta hepatitis lymph nodes
Connective Tissue
Benign
1. Hemangioma of Liver
Epidemiology and Associations:
Most common benign tumour of the liver
Can be seen in all ages, both genders
Morphology:
Usually found directly beneath liver capsule
Discrete red-blue soft nodules
Large vascular channels separated by thin fibrous connective tissue
Pathological Effects and Complications:
Mostly
symptomless
DIVC
Thrombosis
Rupture and intraperitoneal bleeding
Clinical significance: mistaken for metastatic tumours radiologically
Malignant
Angiosarcoma
Gallbladder Carcinoma
Most common malignancy of the extra hepatic biliary tract
F:M = 2:1
Risk factor: Gallstones (95%)
Simulates chronic cholecystitis
Spread and metastases:
Propensity to invade liver, stomach and duodenum
Metastases to liver, regional lymph nodes
Prognosis is poor
Gross:
Diffuse infiltrative growth (70%)
Polypoid exophytic growth (30%)
Microscopy:
Adenocarcinoma, well to poorly differentiated