Seminar 9 - Hepatobiliary Disease Flashcards
List some of the common causes of acute liver failure
Common causes; accidental/deliberate paracetamol overdose, autoimmune hepatitis, other drugs and toxins, acute hep A and b infections ( E additionally in Asia)
Can also be idiopathic ( 15% of adult cases and 50% in peads
How does cholangiocarcinoma present
Very insidious
Indistinguishable with cholelithiasis symptoms
Very unlikely to preoperatively diagnose - usually found when operating on a sperate cause such as the gallstones
How do you manage hypoglycaemia
Iv glucose 10% at rate of 100ml/hr
Where is GGT found
Found in liver, pancreas, renal tubules and intestines
How does excess iron damage the liver
The excess iron causes free radical overproduction & overactivity
This creates reactive oxygen species which damage the liver and lead to cirrhosis
How does multi-organ failure occur in cases of acute liver failure
It occurs as the patients are in a hyperdynamic circulatory state in ALF (low systemic vascular resistance) which causes circulatory insufficiency and poor organ perfusion leading to failure
DIC may also play a role in the multi-organ failure
Describe the macroscopic appearance of the liver in Wilson’s disease
Variable hepatic changes (minor to massive damage)
Steatosis may be present with focal hepatocyte necrosis
What are RBCs broken down into
Haem and globin
Haem further broken down into bilirubin
Hepatopulmonary Syndrome is most common in which type of liver failure
More common in chronic
Can be seen in acute
Cholangiocarcinoma is most common in which age group
Approximately two-thirds of cholangiocarcinomas occur in patients between 50 and 70 years of age
What are cholangiocarcinomas
Cancers arising from the bile duct epithelium
Gallstones are most prevalent in which sex
More common in women
Where are the majority of cholangiocarcinomas found
most often detected in the fundus
Wilson’s disease requires lifelong treatment - true or false
True
It is chronic, progressive and requires life-long treatment
What is the biliary tree
The system of ducts that carries bile from the liver to either the gall bladder or the duodenum.
What is cholestasis
The reduction or stoppage of bile flow
Cholestasis is basically any condition in which substances normally excreted into bile are retained – usually causing damage
How do you treat a paracetamol overdose
Activated charcoal - if <4 hrs from acute OD Otherwise NAC (N-acetylcysteine)
Which pattern of liver injury is caused by drugs like tamoxifen, irinotecan and methotrexate
A steatohepatitis-like pattern of injury
Around 10% of symptomatic gallstones will have cholecystitis - true or false
True
Chronic liver disease will always have what morphological features
All show varying degrees of fibrosis, injury, repair and regeneration
Which lab test results allow for a diagnosis of PBC
2 of the following features for diagnosis: raised ALP >6m, AMA +ve, characteristic histological findings
List the storage functions of the liver
Glycogen storage
Lipid-soluble vitamins A,D,E,K are stored in the liver, alongside vitamin B12
Iron and copper minerals are stored in the liver.
Which conditions can cause hepatic disease leading to jaundice
Many liver diseases such as cirrhosis or hepatitis
PSC is more common in which countries
PSC is more common in Northern Europe and North America compared with Southern Europe and Southeast Asia
What causes hyperoestrogenemia in liver failure
They will have impaired oestrogen metabolism leading to rising levels
What is the most common outcome for cholangiocarcinoma
Most sadly succumb to disease
What is the function of the gall bladder
It stores about 50 ml of bile which produced by the liver until the body needs it for digestion, at which point it release it
List common gallbladder diseases
Cholelithiasis - gallstones
Acute and chronic cholecystitis
Gallbladder cancer - cholangiocarcinoma
List hepatocellular causes of cholestasis
Causes within the liver
Includes: hepatitis, alcohol related liver disease, PBC, certain drugs, cholestasis of pregnancy and cancer that has spread to the liver
What is produced by the deconjugation of bilirubin in the colon
Urobilinogen
A mix of toxicity and immune mediated hepatocyte destruction is seen in which cause of acute liver failure
Hepatitis
Jaundice caused by unconjugated bilirubin is typically caused by what underlying issues
uptake and conjugation problems
What is prothrombin time a marker of
Liver function and blood coagulation
How do you treat cholecystitis
IV antibiotics and IV fluids
Nil by mouth
US to confirm diagnosis
May require an urgent cholecystectomy if a gallstone ileus
PSC is often associated with which other condition
Inflammatory bowel disease - typically UC
Around 2/3 of PSC patients will have it
Only 8% of UC patients have PSC though
List common causes of acute on chronic liver failure
Chronic hep b infection that’s either medically suppressed but there are now viral mutants not controlled by meds or a superimposed hep D infection on top of chronic hep B
Patients with chronic PSC or fibropolycystic disease with superimposed ascending cholangitis
How do you manage spontaneous bacterial peritonitis
Piperacillin and tazobactam empirically then specific management.
If high risk given ciprofloxacin prophylactically
Which cancers can cause acute liver failure
Leukemia/lymphoma - 33%
Breast - 30%
Colon - 7%
To be classed as acute liver failure, what specification must be met
Symptoms must occur within 26 weeks of the liver injury
Typically occur within 8 weeks
What is a gallbladder empyema.
A type of cholecystitis where the exudate is virtually pure pus
Jaundice caused by conjugated bilirubin is typically caused by what underlying issues
Excretory issues
Describe the microscopic appearance of the liver in haemochromatosis
Iron becomes evident first as golden-yellow hemosiderin granules in cytoplasm of periportal hepatocytes that stain with Prussian blue
You then get progressive deposition in the rest of lobule, bile duct epithelium, Kupffer cells
Hepatopulmonary syndrome can be treated by liver transplantation - true or false
True
If the liver is transplanted the lungs will return to normal within the following year
Some patients with chronic liver failure may be asymptomatic until their disease is advanced - true or false
True
This occurs in around 40% of patients
Describe the macroscopic signs of chronic cholecystitis
Features are variable and sometimes minimal
Serosa is usually smooth and glistening but maybe doubled by fibrosis
Fibrous adhesions represents prior acute inflammation
The wall is variably thickened and has an opaque grey white appearance
The mucosa itself is generally well preserved
The severity of liver damage in paracetamol overdose is dependent on what
The amount taken
The persons GSH reserves
Other medications - long term treatment with cytochrome P450 inducers
Describe the appearance of inflammation and necrosis as seen in alcoholic liver disease
Prominent neutrophils (can satellite around ballooned hepatocytes)
Common lymphocytic infiltrates
Spotty necrosis/apoptosis
Describe the clinical features of acalculus cholecystitis
Clinical symptoms cholecystitis tend to be more insidious since they are obscured by the underlying conditions precipitating the attack
It is harder to diagnose and therefore has a higher mortality
How does Wilson’s cause chronic liver damage
Excessive amounts of copper accumulate in liver This leads to fibrous/granular hardening in soft tissue of liver
Eventually results in cirrhosis
What causes haemochromatosis
Caused by excessive iron absorption, most of which is deposited in the liver & pancreas
Can be hereditary or secondary
Explain how the liver contributes to lipolysis
Fatty acids can undergo B-oxidation in the liver
They are used in TCA cycle or to make ketone bodies - energy
Occurs during stress and fasting
What causes cholestasis of pregnancy
hormonal effects on bile flow during pregnancy
Rapid onset acute liver failure is usually caused by what
A drug/ toxin ( i.e. paracetamol overdose)
Does conjugated bilirubin require albumin for transport
NO
It is water soluble
Which drugs can cause chronic liver failure
Amiodarone Methotrexate Isoniazid Phenytoin Nitrofurantoin Methyldopa
What is happening to the incidence of biliary tumours
The reported incidence has increased in recent years
However, the increase is probably due to improvement in data collection and analysis.
Describe the structure of the gallbladder
A pear-shaped organ which is is about 7–10cm long and dark green in colour
Connects to the hepatobiliary system via the cystic duct
Has a muscular wall which contracts to release bile
Describe the clinical presentation of chronic cholecystitis
Does not have the striking manifestations of the acute form
It is usually characterized by recurrent attacks of steady epigastric or right upper quadrant pain
Nearly all Wilson’s disease patients with neurologic involvement develop eye lesions - true or false
True
What is the main regulator of iron absorption
Hepcidin
In the developed world, what are the most common causes of acute liver failure
Drug induced liver injury
What happens to conjugated bilirubin when it reaches the colon
It is deconjugated in the lumen of the colon by bacterial B-glucuronidases
This produces urobilinogen
What is the histopathologic definition of cholestasis
The appearance of bile within the elements of the liver, usually associated with secondary cell injury
What causes hepatopulmonary syndrome
Caused by dilatation of intrapulmonary capillaries and pre-capillary vessels up to 500um in size
This is potentially caused by the diseased liver not clearing factors such as endothelin 1 that will stimulate endothelial cell production of vasodilators such as NO
Which canicular transport protein is responsible for the movement of phosphatidylcholine (main phospholipid)
Multi-drug resistance 3
How do you manage renal failure
Managed by renal team and may require haemodialysis/haemofiltration
Cholangiocarcinoma is most common in which sex
Slight male predominance
Which pattern of liver injury is caused by drugs like tetracycline, valproic acid and zidovudine
These drugs cause mitochondrial dysfunction which leads to microvesicular steatosis
Where is bilirubin produced
Majority is produced through the breakdown of RBC by reticuloendothelial macrophages in the spleen, liver and bone marrow.
The rest comes from turnover of proteins containing haem in the liver - P450 cytochromes
Smaller bile ducts are involved in PSC - true or false
False - ish
It typically affects the large and medium ducts
Smaller intra-hepatic ducts are not directly involved in inflammation but may have mild injury + prominent ductular reaction due to cholestasis.
You do get atypical cases of small-duct PSC!
Which conditions can cause reduced hepatic uptake of bilirubin
Drug interference
Seen in some Gilberts patients
Describe the natural history of Hep D
Occurs as a co-infection
Causes acute hepatitis which is self-limiting
Superinfection: 80% chronic HDV (minority: clearance
What does low albumin levels suggest
Liver disease such as:
Cirrhosis - decreased production
Inflammation - acute phase response temporarily decreases production
Protein-losing enteropathies or nephrotic syndrome - excessive loss of albumin
Cholestasis will cause a build up of all the substances usually excreted in the bile - true or false
False
Not all substances are retained to the same extent in various cholestatic disorders
In some conditions, serum bile salts may be markedly elevated while bilirubin is only modestly elevated and vice versa.
However, demonstrable retention of several substances is needed to establish a diagnosis of cholestasis
How long does it take acute liver injury to present
Usually manifests within 8 weeks of liver injury with many patients progressing to coma within a week
List the microscopic features of cholangiocarcinoma
Usually characterized by the presence of glands embedded in desmoplastic stroma
In some cases cytologic atypia and stromal response are minimal -> in these instances identification of perineural and vascular invasion help establish the diagnosis
List the macroscopic features of cholecystitis
Gallbladder large and distended - tense
Bright red blotchy violaceous to green-black discolouration imparted by subserosal haemorrhages
The serosa is frequently covered by a fibrous exudate that may be fibrinopurulent in severe cases
Which sex is more affected by PBC
Women - 90% of patients are female
Explain how the liver contributes to protein catabolism
The liver breakdown excess amino acids from the diet and metabolises them to a form that can be used or excreted
How can coagulopathy in liver failure be fatal
will cause intracranial bleeds and DIC
List risk factors for cholesterol gallstones
Specific demographic populations (Native Americans) Age ++ Female (oc pill, pregnancy, hormones) Obesity/metabolic syn. Rapid weight loss
How do you treat Wilson’s
Penacillamine
How can hepatorenal syndrome be fatal
Through fluid overload, secondary infection, organ damage and coma
If left untreated many patients will die in first weeks of the syndrome with 50% dying in 2 weeks and 80 % in 3 months
Describe the macroscopic appearance of the liver in haemochromatosis
Slightly enlarged, dense & chocolate brown colour (dark brown to nearly black liver parenchyma)
Colour is due to extensive iron deposition
Also get fibrous septa development
This creates a small, shrunken liver w/ micronodular pattern of cirrhosis
Which other malignant tumours can arise in the gallbladder
neuroendocrine tumours, squamous cell carcinoma and sarcomas
Which chronic conditions can be caused by haemochromatosis
Cirrhosis
Diabetes
Heart failure
Can lead to organ failure
Describe the pathogenies of pigment gallstones
Pigment gallstones are complex mixtures of calcium salts (insoluble ones from unconjugated bilirubin and inorganic ones)
Disorders that are associated with elevated levels of unconjugated bilirubin in bile increase the risk of developing pigment stones e.g. haemolytic anaemia, severe ileal dysfunction or bypass, bacterial contamination of biliary tree
Which type of chronic liver failure has the slowest rate of progression
PBC
How does hepatopulmonary syndrome present clinically
Presents as dyspnoea and cyanosis
The dyspnoea is worse in the upright position due to gravity exacerbating the ventilation perfusion mismatch
Liver failure patients are already at a higher risk of complications from transplant - true or false
True
Because they are so unwell in the first place
What are the most common causes of death in acute liver failure
Infection
HE
Multi-organ failure
in that order
Describe the pathogenesis of acute on chronic liver failure
There will be established cirrhosis and extensive vascular shunting due to existing chronic liver disease
This means there is a large amount of liver parenchyma with a borderline vascular supply making it vulnerable
If there is a superimposed insult the liver is more likely to decompensate severely causing the acute on chronic liver failure
What is the cause of PSC
The aetiology is not well understood
The frequent presence of circulating serum auto-antibodies, association with autoimmune diseases (UC) and the association with certain HLA haplotypes suggests that PSC is an immune-mediated disorder - though not a classic autoimmune
Likely has a trigger (unknown - environmental or immunological) in a genetically susceptible individual
Theory that effector T-cells which were activated e.g., during colitis, migrate to liver where they recognise a cross-reacting bile duct antigen
Infections or changes to intestinal microbiome recruit mucosal T cells to the liver and incite changes in cholangiocytes causing inflammatory injury
Explain how the liver contributes to lipogenesis
Fatty acids can be synthesised within the hepatocytes
List medications that are cytochrome P450 inducers
carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, rifabutin, efavirenz, nevirapine, and St John’s wort
List the histological appearance of mild chronic cholecystitis
Scattered lymphocytes, plasma cells and macrophages in mucosa and in subserosa
Antibody titres correlate with disease severity or progression in PBC - true or false
False
They do not
Also don’t predict response to therapy
Describe stage 1 of paracetamol toxicity
Occurs in first 24hrs
Can be symptomatic or present with N+V and abdominal pain
What is tested for in LFTs
Alanine transaminase (ALT) Aspartate aminotransferase (AST) Alkaline phosphatase (ALP) Gamma-glutamyltransferase (GGT) Bilirubin Albumin Prothrombin time (PT)
What is the function of bile
Bile is the digestive fluid produced by hepatocytes
It plays a critical role in the elimination of bilirubin, excess cholesterol and aids in fat absorption
Why might you see renal damage in paracetamol
AKI that often accompanies paracetamol toxicity
May see renal tubular necrosis as a result
List causes of chronic liver failure
Main causes; chronic hep b and c infection, NAFLD/NASH, alcoholic liver disease
Additional causes ; PBC, PSC, nodular regenerative hyperplasia, chronic schistosomiasis, fibropolycyctic liver disease, hemochromatosis, a 1 antitrypsin deficiency, Wilsons disease, Budd-Chiari syndrome, autoimmune hepatitis and drugs
Can also be idiopathic
PSC-autoimmune hepatitis overlap occurs more often in which patient group
More common in children than adults
Seen in 35% of childhood cases of PSC
So they also present younger
Only conjugated bilirubin causes jaundice - true or false
False
Can be caused by unconjugated or conjugated bilirubin.
List the histological appearance of advanced chronic cholecystitis
subepithelial and subserosal fibrosis accompanied by mononuclear cell infiltration
What is cholsterolosis
This is when there’s a buildup of cholesteryl esters and they stick to the wall of thegallbladderforming polyps
It is associated with cholesterol gallstones
How do you manage coagulopathy in liver failure
Only given blood products if bleeding is an issue ( FFP and platelets would be given)
May be given phytomenadione 10mgIV
List the microscopic features specific to chronic viral hepatitis caused by Hep C
Prominent lymphoid aggregates/ fully formed lymphoid follicles in portal tracts - portal tracts expand
Steatosis (common)
Bile duct injury
Define acute cholecystitis
Cholecystitis is inflammation of the gallbladder that develops over hours
Usually because a gallstone obstructs the cystic duct
How do you treat alpha 1 antitrypsin deficiency
liver transplant
Which type of bilirubin is found in bile
Conjugated
What is the recommended dosing schedule for paracetamol
500-1,000mg QDS to a maximum of 4,000mg/day
Do abnormal LFTs always mean liver disease
No
Can be abnormal in around 17% of the population and normal LFTs doesnt always exclude liver disease.
How can you treat the pruritus in PBC
1st line: Antihistamines (mild-mod itch)
2nd line: Cholestyramine and colestipol (bile binding resins)
3rd line: rifampicin
Which enzyme is responsible for the deconjugation of bilirubin in the colon
Bacterial B-glucuronidases
What is cholecystitis
Inflammation of the gallbladder
May be acute, chronic or acute superimposed on chronic
It’s almost always occurs in association with gallstones
Describe the clinical presentation of PSC
Patients may be asymptomatic at diagnosis - around 50%
Some will present with or develop symptoms of pruritus and jaundice.
Ascending cholangitis, chronic pancreatitis and chronic cholecystitis can also be the PC
How do you treat PSC
No effective medical therapy is available.
Cholestyramine (bile acid-binding resin) used to alleviate pruritus.
Endoscopic dilatation or stenting can relieve biliary obstruction
Liver transplantation is the only treatment option for patients with advanced liver disease
Describe the injury pattern seen in idiosyncratic reactions in drug induced liver disease
Causes a hepatocellular pattern of injury
This can lead to acute hepatitis dominated by inflammation & necrosis
Similar to viral & autoimmune hepatitis
Centrizonal necrosis
Cholelithiasis occurs in approximately what percentage of adults
15%
Acute liver failure caused by toxic injuries typically have which pathological features
Tend to not show scar formation or regeneration because they take place over hours to days - not enough time for formation
May see confluent necrosis in the perivenular region and preserved areas of normal liver
Define chronic liver failure
Progressive destruction of the liver parenchyma that occur over a period greater than 6 months
Results in fibrosis and cirrhosis
List the common signs and symptoms of PBC
Fatigue
Pruritus
Symptoms slowly increase over time
Also get hypercholesterolaemia (xanthelasmas), steatorrhea and vitamin D malabsorption related osteomalacia May see hyper-bilirubinaemia – jaundice RUQ pain Other autoimmune diseases Splenomegaly ± portal HTN (Adv. Disease)
OR could be asymptomatic
Describe the LFT pattern seen in hepatocellular injury
Raised ALT and AST - released from the injured hepatocytes
Acute: raised ALT and AST, normal/raised ALP and GGT, bilirubin is usually also raised.
Chronic: ALT/AST and ALP/GGT and bilirubin are all normal or raised.
What are the two types of cholestasis
obstructive causes and hepatocellular causes
What are the most common caused of death in chronic liver failure
HE
Oesophageal variceal bleed
Bacterial infections
Hepatocellular carcinoma
Where is albumin synthesised
In the liver
What are the main complications of liver transplant
Most common - Graft infection or Sepsis
Bleeding, clotting, failure or rejection of the liver, bile duct leakage and shrinkage, infection, mental confusion and seizures
The immunosuppression used in the transplantation process can cause osteoporosis, diabetes, high cholesterol and HTN
Describe the natural history of Hep C
Usual outcome: Persistent infection and chronic hepatitis
Chronic disease in 80-90% HCV-infected individuals; 20% progress to cirrhosis
What happens to bile acids once secreted
They can be reabsorbed from the intestines and brought back to the liver (enterohepatic circulation) to be taken up by the hepatocytes
This restores the pool of acids
How can age impact the rate of chronic liver failure progression
increasing age will increase rate of progression
Which conditions can cause impaired bile flow
Obstruction - gallstone, tumour
Cholangiopathies - PBC, PSC
What type of bilirubin is responsible for post-hepatic jaundice
Conjugated
Describe the appearance of the pancreas in haemochromatosis
Intensely pigmented - brown
List the macroscopic features of NAFLD
Cholestasis
Obliterated central veins
What causes PBC
It is an autoimmune disease so likely a mixture of genetics and environment
List some complications from ongoing injury in PSC
Ongoing injury and continued destruction of the bile ducts results in secondary parenchymal damage, fibrosis, cirrhosis, and end-stage liver disease
Those with UC are regularly screened for PSC - true or false
True
A raised ALP is often how the disease is detected in them.
List the macroscopic features of chronic viral hepatitis
Areas of necrosis
Collapse of liver lobules
Seen as ill-defined areas that are pale yellow
How can you treat the osteoporosis in PBC
Increase activity levels (esp. post-menopausal women).
Bisphosphonates, esp. alendronate.
How does bilirubin get into the liver
The bilirubin enters the bloodstream bound to serum albumin and is transported to the liver.
It is taken up by the hepatocytes at their sinusoidal membranes.
Sinusoids are where blood passes through the hepatocytes
Paracetamol is available in which forms
Tablets/ capsules Soluble Liquid Suppositories IV
It and is widely available OTC, either alone or in combination with other analgesics
What type of bilirubin is responsible for hepatic jaundice
May have mixed picture - both conjugated and unconjugated in blood
Does portal HTN develop in acute liver failure
Yes - it develops over days to weeks
Although it is much more common in chronic failure
Which 4 conditions contribute to the formation of cholesterol gallstones
1) supersaturation of bile with cholesterol
2) hypomotility of the gallbladder
3) accelerated cholesterol crystal nucleation
4) hypersecretion of mucus in the gallbladder, which traps the nucleated crystals leading to accretion of more cholesterol and the appearance of macroscopic stones
What is considered a staggered paracetamol overdose
A toxic dose taken over more than 1 hour
>150mg/kg within 24hrs may produce serious toxicity
What are the two main types of gallstones
Cholesterol stones - composed mainly of crystalline cholesterol monohydrate
Pigment stones - composed mainly of bilirubin calcium salts
Most cases are a mix of both.
PSC is common in smokers - true or false
False
It is a disease of non-smokers
How can ascites be fatal
Can develop spontaneous bacterial peritonitis
Bacteria, usually E. coli, strep pneumonia or klebsiella, seep through the peritoneal membrane from the GI tract to cause inflammation and infection
Acalculus cholecystitis is more common in which patient populations
The incidence is higher in the intensive-care population, particularly in patients in burn and trauma units.
The pain in biliary colic is colicky - true or false
False
It’s a misnomer - the pain is usually constant
Which pattern of ALT and ALP suggests hepatocellular injury is the main cause
More than 10-fold increase in ALT and a less than 3-fold increase in ALP
What controls the movement of bile etc through the major duodenal papilla
Papilla is regulated by the sphincter of odi
List the microscopic features of alcoholic liver disease
Liver inflammation (alcoholic hepatitis) & Fibrosis: Prominent
Ballooned hepatocytes
Inflammation & necrosis
Perivenular/Pericellular fibrosis
AMA positivity is quite specific for PBC - true or false
True
98% specificity
List the microscopic features of NAFLD
Steatosis, Lobular inflammation, Ballooned hepatocytes
Steatosis appears as mixed small and large fat droplets
When established: steatosis/ballooned hepatocytes may be reduced or absent
Mallory hyaline, Neutrophilic infiltrates
Fibrosis develops around central vein as a fine “chicken wire pattern” of pericellular collagen deposition - individual and clustered hepatocytes are surrounded by thin scars
This can progress to periportal and bridging fibrosis and eventually cirrhosis
How do the bile constituents leave the liver
All of the bile constituents are moved across the canicular membrane of the hepatocytes by a variety of transporter proteins.
What are the characteristic features of PBC
Characterised by inflammatory destruction of small- and medium-sized intrahepatic bile ducts
Eventually the ducts will be lost and fibrosis develops as a consequence
Describe the pathogenesis of PBC
Starts with an unknown trigger - genetic or environmental
Could be something like infection or chemicals in genetically susceptible individuals
The trigger leads to the formation of auto-antigens against bile duct epithelial cells
T-lymphocytes will then start to attack auto-antigens” expressed on bile duct cells
This leads to injury which causes retention of bile salts (toxic substances build up) and secondary hepatocellular injury occurs
Anti-microbial antibodies (AMAs) also play a role
What type of enzyme is responsible for haem being broken down to bilirubin
Phagocytic enzymes
What are the effects of hyperoestrogenemia in liver failure
Palmar erythema - due to local vasodilatation)
Spider angioma - central arteriole that is dilated and pulsating with small vessels radiating from it
Hypogonadism - causing testicular atrophy, hair loss and gynaecomastia in men
Explain how the liver contributes to glucose metabolism
Excess glucose is stored as glycogen in the liver and can be converted back to glucose when required (e.g. exercise)
The liver can also generate glucose (gluconeogenesis) through the conversion of amino acids, lactate, pyruvate and glycerol
How does acute liver failure cause cholestasis
Due to alterations of bile formation and flow causing retention of bilirubin and other solutes that are normally eliminated in bile
All of the clinical signs and manifestations of ALF can also occur in CLF - true or false
True
List some of the pre-cursor lesions for cholangiocarcinoma
Flat in-situ lesions with varying degrees of dysplasia
Mass forming adenoma-like lesions termed intracystic papillary tubular neoplasm
Intestinal metaplasia.
Fat-soluble vitamin deficiencies are a common complication of cholestasis in children - true or false
True
May require administration of fat-soluble vitamins and monitoring
The distribution and incidence of acute cholecystitis follow that of which other disease
Cholelithiasis (gallstones)
because of the close relationship between the two.
What are the pathological characteristics of PSC
Inflammation and injury of the medium- and large-sized bile ducts, leading to fibrosis and multi-focal stricturing of the ducts
What is the characteristic sign of bile duct injury in drug-induced liver disease
Characterised by varying combinations of cholestasis & ductular reactions
This can lead to chronic cholestasis
List the pathological features of acute liver failure
Most commonly has massive hepatic necrosis and broad areas of parenchymal loss which will be surrounded by islands of either preserved or regenerating hepatocytes
Affected livers are usually small and shrunken and may be soft and congested
Rarely ALF may have widespread liver cell dysfunction without obvious cell death
What does an increase in PT suggest
Liver disease/dysfunction.
The risk of gallstones becoming symptomatic increases with time - true or false
False
the risk diminishes with time
Describe the appearance of the heart in haemochromatosis
Enlarged heart with hemosiderosis (striking brown coloration)
List the macroscopic features of alcoholic liver disease
Enlarged, soft, yellow, greasy - fatty liver
Fatty change: completely reversible if abstention from further intake of alcohol
Macrovesicular steatosis - predominant;
(Unusual) Microvesicular steatosis: alcoholic foamy degeneration
Seen in chronic heavy alcohol use
This is also associated with ER & mitochondrial damage
Describe the pathological features of cholate stasis as seen in PBCs
Causes swelling of periportal hepatocytes (clear cytoplasm’s w/ granular strands, aka. feathery degeneration)
May develop Mallory hyaline.
List morphological features of chronic liver disease
Cirrhosis
Fibrosis - pattern will vary with cause
Parenchymal nodules - variable size
Vascular thrombosis - extent varies
How does HE present
Will present with rigidity, hyperreflexia and asterixis
It has the potential to cause seizures and cerebral oedema (and the associated symptoms)
How can the ALT/AST ratio be used to analyse LFTs
Can indicate the cause
ALT > AST suggests chronic liver disease
AST > ALT suggests cirrhosis and acute alcoholic hepatitis
Describe the mechanisms of liver injury in haemochromatosis
Lipid peroxidation via iron-catalyzed free radical reactions
Stimulation of collagen formation by activation of hepatic stellate cells
Interaction of ROS and iron with DNA - leads to lethal cell injury (predisposes the person to HCC)
Which compounds make up bile
Bilirubin, bile salts, cholesterol and phospholipids.
List the general histological appearance of chronic cholecystitis
Inflammation variable
Rokitansky-Aschoff sinuses - forms a pocket?
Other findings – porcelain gallbladder (very rare), hyalinizing cholecystitis, xanthogranulomatous cholecysitis and hydrops of the gallbladder
Toxic brain injury in Wilson’s disease occurs in which region
Involves the basal ganglia
Which age group is most affected by cholestasis
Cholestasis is observed in people of every age group
However, newborns and infants are more susceptible due to immature livers
What is considered an acute paracetamol overdose
A toxic dose taken within 1 hour
>75mg/kg is generally considered the threshold for serious toxicity
What are the most common causes of decompensation in chronic liver disease
GI bleeds, high alcohol intake, alcoholic hepatitis or drug induced liver injury
BUT no cause is found in 50% of decompensations
Which cause of acute liver failure is associated with scarring
Viral infection
Will also see regeneration
This is because the insult occurs over weeks to months so has time to occur
Which type of bilirubin can be excreted in the urine
Conjugated
This is because it is water soluble
Therefore can be picked up on urine tests
What causes idiosyncratic drug induced liver disease
Often antimicrobial drugs
Occur after 1-3 months of exposure
List the mechanisms of hepatocyte injury & inflammation in alcoholic liver disease
Acetaldehyde (product of alcohol dehydrogenase)
CYP2E1 induction
Impaired methionine metabolism
Damage caused by these causes inflammation
With chronicity you get
liver fibrosis & deranged vascular perfusion
List some of the manifestations of acute liver failure
Cholestasis Hepatic encephalopathy Coagulopathy Ascites Portal HTN Hepatorenal syndrome Hepatopulmonary syndrome Multiorgan failure
Also infections, circulatory collapse and metabolic acidosis and renal failure
List the metabolic functions of the liver
Maintenance of blood glucose (carbohydrate metabolism)
Lipid metabolism – both lipogenesis and lipolysis
Protein synthesis
Protein catabolism
Ammonium metabolism
Vitamin D activation
Gallstones are most prevalent in which age group
Middle-aged to old people
How does liver size change in acute liver failure
They initially will have an enlarged liver due to hepatocyte swelling, inflammatory infiltrate and oedema but it will shrink dramatically as the parenchyma is destroyed
Which sex is more affected by cholecystitis
Women - 3 times more common
Up to the age of 50 years, and is about 1.5 times more common in women than in men thereafter
List pathological signs of paracetamol overdose
Cytolysis with centrilobular necrosis
Most patients with calculus cholecystitis will present with jaundice - true or false
False
Most patients are free of jaundice
List the pathological features of cholsterolosis
Strawberry gallbladder - looks like one
Foamy lipid laden macrophages in the lamina propria
Can you treat the liver disease in α1- antitrypsin deficiency
No treatment but supportive care of chronic liver disease complications
May become chronic
What is the most common cause of acute cholecystitis
90% of cases caused by gallstone
The other 10% are acalculus
What causes hepatorenal syndrome
Portal hypertension is the triggering event
Confounded by increased production of vasodilators by endothelial cells in the splanchnic vasculature
This causes systemic vasodilatation and renal hypoperfusion leading to RAAS activation
In the setting of Portal Hx and persistent vasodilator release the main effect of RAAS is to further reduce GFR and renal perfusion = renal failure
At what serum bilirubin level does jaundice usually become evident
Above 2-2.5mg/dL (normal level is between 0.3 and 1.2 mg/dL)
If a gallstone migrates into the common bile duct, how might the patient present
Jaundice
Cholangitis
Acute Pancreatitis
List the microscopic features of cholecystitis
Early changes of acute cholecystitis include oedema congestion and mucosal erosion.
neutrophils are sparse unless there is superimposed infection
What is primary biliary cholangitis
It is a chronic autoimmune disease in which the intrahepatic bile ducts i are slowly destroyed.
Previously called primary biliary cirrhosis
What can happen to other body tissues when levels of unconjugated bilirubin get too high
The amount that is unbound (instead of bound to albumin) also rises and can exert its toxic effect on the tissues
In brain it causes neuro issues such as kernicterus
Describe stage 4 of paracetamol toxicity
Occurs after 96 hours or more
The resolution phase
Clinical recovery and normalisation of LFTs in 3-4 weeks
Complete histological recovery will take several months
What is primary sclerosing cholangitis
It is a chronic progressive cholestatic liver disease, characterised by inflammation and fibrosis of the intrahepatic and/or extrahepatic bile ducts, resulting in diffuse, multi-focal stricture formation.
Preserved segments become dilated
How do you manage gallstones
Start with painkillers, low fat diet and weight loss and observe for 3-6 months
If Recurrent episodes of pain / colic then consider / refer for surgery
Cholecystectomy is the surgery of choice (usually laparoscopic)
If unfit for surgery – Ursodeoxycholic acid 10mg/kg/day
Describe the path of bile from the
It is released from hepatocytes in the liver and travels via canaliculi to intralobular ducts then the collecting ducts before entering the left and right hepatic ducts.
These converge to form the common hepatic duct.
This duct is joined by the cystic duct which connects to the gall bladder.
This meeting point is the beginning of the common bile duct.
The CBD passes posteriorly to the first part of the duodenum and head of the pancreas before joining the main pancreatic duct.
This forms the hepatopancreatic ampulla (commonly known as the ampulla of Vater).
Both ducts can empty into the second part of the duodenum via the major duodenal papilla.
How does wealth affect the prevalence of gallstones
Affects 10-20% of adults in high income countries, uncommon in low-income countries
In the developed world, what are the most common causes of chronic liver failure
Alcoholic liver disease
Chronic hep B and C infections
NAFLD/NASH
Haemochromatosis
PSC is more common in which sex
Men
male-to-female ratio of 2:1
What is involved in phase I drug metabolism
Phase I metabolism consists of reduction, oxidation, or hydrolysis reactions.
These reactions serve to convert lipophilic drugs into more polar molecules by adding or exposing a polar functional group
List the requirements for transplant in acute liver failure
PT >20 seconds or INR >2.0 pH < 7.3 or [ H+] > 50 Hypoglycemia Conscious level impaired Creatinine > 200 mmol/l Any patient with encephalopathy, coagulopathy or renal impairment
What is a common side effect of oral ursodeoxycholic acid
Diarrhoea or pale stools
Is there a morphological difference between calculus and acalculus cholecystitis
Not specifically
The only real difference is the presence or absence of the calculus
