(59a) Diseases of the Hepatobiliary system Flashcards
Name 3 medical liver diseases
- jaundice
- hepatitis
- cirrhosis
What is the commonest sign of liver disease?
Jaundice
When is jaundice visible and where?
When bilirubin is higher than 40umol/l
First visible in the sclera of the eye
What are the 3 types of jaundice?
classified according to where the abnormality is in the metabolism of bilirubin
- pre-hepatic
- hepatic
- post-hepatic
What are the causes of pre-hepatic jaundice?
Too much bilirubin produced
- haemolytic anaemia
What is bilirubin?
The yellow breakdown product of normal heme catabolism, caused by the body’s clearance of aged red blood cells which contain hemoglobin. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases
What are the causes of hepatic jaundice?
Too few functioning liver cells
- acute diffuse liver cell injury
- end stage chronic liver disease
- inborn errors
What are the causes of post-hepatic jaundice?
Bile duct obstruction
- stone or structure
- tumour of the bile duct or pancreas
Describe the pathway of bilirubin metabolism
- bilirubin is produced by red blood cell breakdown (unconjugated)
- metabolised in the liver (conjugated) and excreted in bile
- some bilirubin is re-absorbed from the gut (enterohepatic circulation)
- also bile salts
Where are erythrocytes broken down and unconjugated protein-bound bilirubin produced?
In the spleen
Where does conjugation of bilirubin occur? (becomes water-soluble)
In the liver
Where is urobilinogen produced?
In the intestines
Which protein carries unconjugated bilirubin?
Albumin
Describe the difference in solubility between unconjugated and conjugated bilirubin?
Unconjugated bilirubin = lipid-soluble
Conjugated bilirubin = water-soluble
What happens to conjugated bilirubin after the liver?
It is excreted in bile into the small intestine through the bile duct
What happens to conjugated bilirubin once it is in the small intestine?
Gets to ileum or first part of large intestine and is converted to urobilinogen (urobilinogen = lipid-soluble)
Most urobilinogen is oxidised to what?
Sterocobilin
Sterocobilin is responsible for what?
The brown colour of faeces
Describe the bilirubin in pre-hepatic jaundice
- unconjugated
- bound to albumin
- insoluble
- not excreted
What would the signs be in pre-hepatic jaundice?
Yellow eyes and skin only
Describe the bilirubin in hepatic jaundice
- mainly conjugated
- soluble
What would the signs be in hepatic jaundice?
Yellow eyes and dark urine
Describe the bilirubin in post-hepatic jaundice
- conjugated
- soluble
- excreted
- but can’t get into gut
What would the signs be in post-hepatic jaundice?
Yellow eyes, pale stools and dark urine
The site of abnormality of bilirubin excretion can be deduced from what?
Clinical history of skin, urine and faeces colour
Why are liver enzymes measured in liver function tests?
Damage to cells in the liver causes enzymes to leak from the cells
Which enzymes leak from damaged hepatocytes? (measured in liver damage tests)
- ALT (alanine aminotransferase)
- AST (aspartate aminotransferase)
What leaks damaged bile ducts? (measured in liver damage tests)
Alkaline phosphate
What 3 things are measured in liver function tests?
- bilirubin
- albumin
- clotting factors
What would raised conjugated bilirubin without extrahepatic duct obstruction indicate?
Disease of hepatocytes or intrahepatic ducts
Why are clotting factors and albumin measured in LFTs?
They are manufactured by hepatocytes - so levels fall when insufficient liver synthetic function
When would albumin levels be low?
In chronic liver disease (has a long half life)
could also be due to insufficient dietary intake, or nephrotic syndrome causing increased urinary excretion
When would clotting factors be low?
Acute liver disease and liver failure (short half life)
Why is poor clotting also seen in patients with obstructive jaundice?
Can’t absorb fat-soluble vitamins (vitamin K)
What is the first histopathological feature in the liver of obstructive jaundice?
Bile in the liver parenchyma (jaundice in skin)
What are the further signs of obstructive jaundice with increasing time?
- portal tract expansion
- oedema
- ductular reaction (proliferation of ductules around the edge)
- bile salts and copper cannot get out (accumulate in hepatocytes, bile salts in skin = itchy)
Eventually, severe chronic liver disease and cirrhosis
What is used to first investigate a patient with jaundice?
Ultrasound scan (USS) to check for bile duct dilatation - if ducts are not dilated, then lover biopsy may be performed to investigate cause of jaundice
What is seen on obstructive jaundice, perivenular (zone 3) changes?
Bile pigment is visible in bile plugs which show that bile has been excreted by hepatocytes into intracellular canaliculi but accumulated because of low bile flow
- also get swelling and irregularity of hepatocytes, and increased activity of Kupffer cells phagocytosing dead hepatocytes
Were are the changes to the portal tract in obstructive jaundice?
Gets larger, initially due to swelling (oedema, tissue looks pale) then you get ductular reaction (increased number of small bile ducts around periphery of tracts) and some associated inflammatory cells including neutrophils
Over time, oedema reduces and fibrosis increases - characteristic appearance = biliary gestalt
Most non-obstructive cause of jaundice are due to what?
Acute hepatitis
What is acute hepatitis?
Inflammation in the liver, can only really be seen with liver biopsy (no classical pain and swelling etc) - symptoms usually mild/non-existant unless severe - recent onset and will resolve back to normal if cause does not persist
What is chronic hepatitis?
Present for over 6 months, results in ongoing liver cell injury and progressive structural liver damage of scarring and remodelling
The severity of acute hepatitis depends on what?
How many hepatocytes are damaged at once, and how good the liver regeneration is
What is at the most severe end of the spectrum in acute hepatitis?
- coagulopathy
- encephalopathy (confusion, coma)
- death
What are the causes of acute hepatitis?
- inflammatory injury (viral, drugs, autoimmune, unknown = seronegative)
- toxic/metabolic injury (alcohol, drugs eg. paracetamol)
Which viruses can causes severe inflammatory injury (acute hepatitis)?
Hepatitis A, B, E
What is DILI?
Drug-induced liver injury
How is the overall appearance of acute hepatitis on biopsy described?
Lobular disarray
What is seen on biopsy in acute hepatitis?
- apoptotic hepatocytes (acidophil body) = spotty necrosis
- inflammatory cells
- hepatocytes vary in size
Overall = lobular disarray
What is seen on biopsy in the more severe end of the spectrum of acute hepatitis?
Whole confluent areas of necrosis of hepatocytes = confluent panacinar necrosis
What is acute hepatitis with bridging necrosis?
Intermediate-severity acute hepatitis
Confluent necrosis of adjacent hepatocytes in a ‘bridge’ between a portal tract and hepatic vein
What are the 5 groups of causes of chronic hepatitis?
- immunological injury
- toxic/metabolic injury (fatty liver disease)
- genetic inborn errors
- biliary disease
- vascular disease
What is the most common group of causes of chronic hepatitis?
Toxic/metabolic injury
What can identify which of the 5 groups is the causes of chronic liver injury?
Liver biopsy
What are the immunological causes of chronic liver injury?
- virus
- autoimmune
- drugs
What are the toxic/metabolic causes of chronic hepatitis (fatty liver disease)?
- alcohol
- non-acoholic fatty liver disease (NAFLD)
- drugs
What are the genetic inborn errors causes of chronic liver injury?
- iron
- copper
- alpha1antitrypsin
What are the biliary disease causes of chronic hepatitis?
- autoimmune
- duct obstruction
- drugs
What are the vascular disease causes of chronic hepatitis?
- clotting disorders
- drugs
Describe the non-specific pathology of chronic liver disease?
Injury to liver cells, inflammation, formation of scar tissue and regeneration of hepatocytes
Specific pathology of chronic liver disease depends on what?
The cause of injury
What are the uses of liver biopsy in diagnosis of chronic liver disease?
- determine the causes of damage
- asses the stage of the stage (how much scarring, spectrum from normal to cirrhosis)
Describe how scarring progresses in chronic liver disease
Scarring gradually increases and starts to link vascular structures (bridging) - eventually transforming the liver into separate nodules = end stage = cirrhosis
What are the 4 general stages of scarring in chronic liver disease
- normal
- portal fibrosis
- bridging fibrosis (from portal tract to hepatic veins)
- cirrhosis
What are the hepatotrophic trophic viruses?
Ones that specifically infect the hepatocytes causing liver disease (hepatitis A, B etc)
D = delta, only seen in people with B E = waterborne, zoonosis, pigs
What other viruses (not hepatotrophic) can cause hepatitis as part of systemic disease?
- EBV
- CMV
- HSV
Which hepatitis viruses are major causes of liver disease worldwide?
B and C
hepatitis A does not cause chronic liver disease
What is the treatment for hep B and C?
Hep B = IFN, lamivudine + new ones
Hep C = IFN, ribavirin + new ones
What is the prophylaxis for hep B and C?
Hep B = vaccine, Ig
Hep C = none
What is the spectrum of liver pathology due to alcohol?
- fatty change
- alcoholic steatohepatitis
- cirrhosis
Some patients with metabolic syndrome have a similar pathology of liver disease to that causes by alcohol. What is this called?
Non-alcoholic fatty liver disease (NAFLD)
The combination of which 2 risk factors in synergistic in causing liver disease?
Alcohol and obesity
A liver biopsy showing features of steatohepatits is likely to be due to what?
Alcoholic liver disease
Some patients with alcohol injury may just show fatty change; what is this?
A reversible stage of liver injury that may or may not progress to steatohepatitis?
How is steatohepatitis seen on liver biopsy?
- white blobs = steatosis
- ballooned hepatocyte with mallory body
- inflammatory cells
- pericellular fibrosis (around hepatocytes)
- fibrosis in portal tracts
What is Van Gieson stain?
The simplest method of differential staining of collagen and other connective tissue (used in liver biopsies)
Describe the pathology of NAFLD?
Same pathological spectrum as alcoholic liver disease (steatosis, steatohepatitis, cirrhosis, HCC)
NAFLD is associated with what?
Metabolic syndrome - obesity, type 2 diabetes, hyperlipidaemia, also some drugs
What is the commonest cause of liver disease?
Metabolic syndrome
What is the treatment for NAFLD?
Address the causes of metabolic syndrome
What is steatosis vs steatohepatitis?
Steatosis = fatty change
Steatohepatitis = fatty chnage plus hepatocyte injury - ballooning, Mallory Denk body, inflammation, sinusoidal fibrosis
Why is there injury to liver cell mitochondria in NAFLD?
Mitochondria injured by oxidative stress of too much energy transfer (too many calories)
What is there a risk of in any cause of cirrhosis?
Hepatocellular carcinoma
Drug-induced liver injury (DILI) is iatrogenic; what does this mean?
Induce inadvertently by a doctor/medical treatment/diagnostic procedures
Hepato-toxic drugs
DILI can be classified into which 2 categories?
- intrinsic (anyone taking drug is likely to get liver damage, predictable eg. paracetamol)
- idiosyncratic (depends on individual susceptibility, metabolic/immunoligcal) - rare and can be severe
What is the commonest symptom of DILI?
Jaundice
How is the type of acute liver injury decided?
Ratio of liver enzymes ALT: alk phos - classified at hepatitic, cholestatic, or mixed
Hepatic and mixed forms = risk of severe disease and liver failure
over 5 = hepatocellular
under 2 = cholestatic
2-5 = mixed
In the diagnosis of DILI, what other causes should be excluded?
- alcohol and NAFLD
- acute presentation of underlying chronic liver disease
- autoimmune
- biliary
- vascular
Which drugs should patients avoid?
Any that have caused injury in the past
Antibiotics are the commonest cause
(any drug can cause liver injury and can cause diff injury in diff patients, time of onset is variable, usually improves on stopping drug)
What are the standard criteria for DILI?
- onset of abnormal LFTs after intake of drug
- improvement in LFTs after stopping drug
- alternative causes excluded by detailed investigation, including liver biopsy
- increase in LFTs by 100% in re-challenge
Drug induced if all of first 3 or 2 + positive re-challenge
What is the commonest cause of acute liver failure in the UK?
Paracetamol toxicity
How is paracetamol seen on liver biopsy?
Results in necrosis of a high proportion of hepatocytes in a predictable, zonal distribution, without any inflammation
Hepatocytes around the portal tracts are spared and able to regenerate the liver back to normal if toxicity is not too severe
What is the difference between safe and unsafe paracetamol metabolism?
2 safe metabolic pathways (metabolised by glucuronyl transferase or sulphotransferase)
Too much paracetamol = metabolised by cytochrome P450 pathway to a toxic metabolite (NAPBI)
What can be given to neutralise paracetamol overdose?
Glutathione
If glutathione is not given in the case of paracetamol overdose, what happens to the toxic metabolite?
It bind covalently to tissue membrane proteins and causes necrosis - irreversible cell death
How is paracetamol toxicity treated?
Treatment with IV N-actetyl cysteine - resorts glutathione
Avoids liver cell damage
What is cirrhosis?
A diffuse hepatic process characterised by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules
End point of chronic liver disease
Why can the liver not perform properly when cirrhotic?
Liver cells still present, but portal vein blood bypasses the sinusoids so liver cells cannot perform their functions
Why do you get portal hypertension in cirrhosis?
As the pressure inside the liver increases
What are the causes of cirrhosis?
- alcohol
- non-alcoholic steatohepatitis (metabolic syndrome)
- chronic viral hepatitis (B and C)
- autoimmune liver disease (primary biliary cirrhosis, primary sclerosing cholangitis)
- metabolic (iron, copper, alpha 1 antitrypsin)
Describe the appearance of cirrhosis microscopically
- regenerative nodules of hepatocytes
- surrounded by sheets of fibrous tissue
In cirrhosis (the ned stage of all chronic liver disease), the liver is converted into what?
A mass of regenerating nodules wrapped by fibrous scar tissue
What are the complications of cirrhosis due to structural changes and fibrosis?
- portal hypertension
- increased blood flow, stiff liver
- pressure rises in portal vein
- oesophageal varices (bleeding can cause massive haemorrhage)
What are the complications of cirrhosis due to liver cell failure?
- fewer hepatocytes and blood bypasses sinusoids
- synthetic - oedema, bruising, muscle wasting
- detoxifying - drugs, hormones, encephalopathy
- ascites - low albumin, portal hypertension, hormone fluid retention (aldosterone)
- excretion: bile - jaundice, bile salts - itching
Why are patients with cirrhosis vulnerable to infections?
Liver is an important site of immune response (reticulo-endothelial cells)
Cirrhosis is a major risk factor for what?
Hepatocellular carcinoma
What is the role of liver biopsy in chronic liver disease?
- stage of disease
- cause of disease
- current activity
- response to treatment (if previous biopsies)
The benefits of definite diagnosis from liver biopsy is balanced against what?
The risks of haemorrhage and puncture of other organs
Name 3 metabolic disease in adults that can be diagnosed by specific changes on liver biopsy
- alpha 1 antitrypsin deficiency
- haemochromatosis
- Wilson disease
Describe the effect alpha 1 antitrypsin deficiency on the liver
- A1AT is made in the liver and excreted into the blood where it neutralises proteolytic enzymes (anti-protease)
- abnormal structure of A1AT means it cannot be excreted from hepatocytes
- accumulated A1AT forms globules of glycoprotein
- this damages liver cells and may cause fibrosis and cirrhosis
How are globules of glycoprotein due to accumulation of A1AT seen on biopsy?
PAS diastase stain - stain positive
How does alpha 1 antitrypsin affect the lungs?
Low levels of A1AT in the serum - failure to inactivate neutrophil enzymes - makes the patient susceptible to emphysema (particularly if they also smoke)
What is haemochromatosis?
Abnormality of HFE gene causing failure of iron absorption regulation leading to excess iron accumulating in various organs “bronzed diabetes”
Excess iron in liver causes…
Liver injury and eventually cirrhosis as well as high risk of hepatocellular carcinoma
Excess iron in pancreases causes…
Diabetes
Excess iron in skin causes..
Pigmentation
Excess iron in joints causes…
Arthritis
Excess iron in heart causes…
Cardiomyopathy
Patients with haemochromatosis have high serum levels of what?
Transferrin, and high transferrin saturation
How is haemochromatosis treated?
Venesection - deplete iron stores to normal
Which stain is used on liver biopsies for haemochromatosis?
Perl’s stain: blue = iron
What is Wilson disease?
Inborn error of copper metabolism (rare)
In Wilson disease, where does copper accumulate?
- liver
- eyes
- brain
But low serum copper due to low caeruloplasmin (copper transport protein)
High urinary copper
What does copper accumulation in the liver cause?
Cirrhosis
What does copper deposition in the eyes cause?
Kayser-Fleischer rings (ring around the iris)
What does copper accumulation in the brain cause?
Ataxia etc.
How are live biopsies stained to see Wilson disease?
Rhodanine stain: copper = brown
Biopsy can also be sent to measure amount of copper in grams per dry weight liver tissue
What is the treatment for Wilson disease?
Chelate copper and enhance its excretion
Some patients with Wilson disease present in what way?
With acute liver failure and haemolysis - this is life-threatening and an indicate for super-urgent liver transplantation
What are the systemic effects of liver failure (physical signs of cirrhosis)?
- ascites
- muscle wasting
- bruising
- gynaecomastia
- spider naevi
- caput medusae
What is ascites?
Abdominal swelling due to fluid accumulating in the peritoneal cavity
What are spider naevi?
Small clusters of dilated capillary vessels in the skin due to hormone imbalance
What is kaput medusae?
Dilated veins radiating around the umbilicus in patients with severe portal hypertension, due to recanalisation of the embryonic vitelline vein to the umbilicus
What is portal hypertension?
High pressure in hepatic portal vein, bringing blood from GI tract to liver - due to increased stiffness of liver due to fibrosis and hyper dynamic circulation
What are the complications associated with portal hypertension?
- splenomegaly = low platelets
- oesophageal varices = risk of haemorrhage
- piles (perianal varices)
- part of cause of ascites
The main causes of portal hypertension can be divided into which 3 categories?
- pre-sinusoidal
- sinusoidal
- post-sinusoidal
What are the post-sinusoidal causes of portal hypertension?
Hepatic vein thrombosis = Budd Chiari syndrome
What are the sinusoidal causes of portal hypertension?
Cirrhosis (disease within liver parenchyma)
What are the pre-sinusoidal causes of portal hypertension?
- portal fibrosis in cirrhosis
- non-cirrhostic portal hypertension eg. sarcoid, schistosomiasis, portal vein thrombosis
Describe post-sinuoidal portal hypertension
Blood can’t flow out of liver due to obstruction between intrahepatic branches of hepatic veins and right atrium
Budd Chiari syndrome is associated with pro-coagulant clotting syndrome
Causes ascites and hepatomegaly
Can be treated by stunting veins and anticoagulation
Describe sinusoidal portal hypertension
Liver insufficiency so patients have ascites (low albumin, disrupted metabolism of aldosterone) - so risk of developing liver failure if they have shunt procedure
Describe pre-sinusoidal portal hypertension
Liver cell function is well preserved and patient has problems from oesophageal varices and splenomegaly but not ascites - can beg treated by shunt procedure to decompress the portal vein into the hepatic vein
