BM423 - Block B (the liver)

what is the most common cause of liver disease in Scotland?

alcohol

in terms of size, what is the liver?

largest organ in the body

where is the liver located?

upper right quadrant of abdomen

describe the general structure of the liver?

divided into four lobes (left, right, caudate, and quadrate)

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capable of regeneration

what is the major function of the liver?

metabolism (central role)

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carried out by liver cells (hepatocytes) (constitue 60% of the liver mass)

what are the various functions of the liver? (7)

glucose metabolism (gluconeogenesis and glycogen synthesis)

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fat metabolism (cholesterol synthesis/excretion and bile production (aids fat digestion))

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protein metabolism

(synthesis of plasma proteins) (urea synthesis) (nitrogen removal)

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endocrine synthesis/metabolism

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toxin/drug metabolism and excretion

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storage (glycogen, vitamins, minerals)

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biliubin metabolism/excretion

are LFTs diagnostic?

no - but they provide information about the state of a patient's liver

what two damage patterns can liver damage present with, as suggested by LFTs?

hepatocellular injury (i.e., cell damage) or cholestatic pattern (i.e., blockage somewhere)

how are LFTs involved with liver disease?

they can detect the presence of liver disease and follow the progress

what sample is required from a patient in order to carry out LFTs?

serum

what do LFTs involve? (the various tests)

- serum bilirubin

- aminotransferases (AST/ALT)

- alkaline phosphatase (ALP)

- serum albumin

- gamma-glutamyl transferase (GGT)

why are ALT/AST assessed as part of the LFT?

they are enzymes found in hepatocytes that will leak into the blood when the cells are injured

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their presence in serum indicates hepatocellular injury (can measure activity of enzyme)

when would ALT/AST increase?

in hepatitis, toxic injury (e.g., drug overdose), ischaemic shock

in terms of specificity/sensitivity, what is true for ALT and AST as markers for liver cell damage?

they are sensitive but non-specific markers of liver cell damage

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AST is less specific to the liver as it is also increased in muscle damage and haemolysis

where is ALP normally found?

cells lining the bile duct

when does ALP tend to increase?

in cholestasis (blockage of bile flow)

where can ALP be found aside from in the liver?

in the bone, small intestine, placenta (in third trimester), and kidney

in what demographic does ALP tend to be higher? why?

growing children (bone ALP/bone growth)

what else would need to be elevated for an elevated ALP to mean there is liver damage?

GGT (gamma-glutamyl transferase)

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if ALP and GGT are elevated, suggests liver is source of increased ALP activity

where is GGT normally found?

widely distributed in tissues (including liver and kidney)

when is GGT activity elevated/effected?

raised when there is cholestasis

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affected by ingestion of alcohol and drugs (such as phenytoin (anti-epileptic))

what is bilirubin? where is it normally found?

a breakdown product of haem

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normally found in haemoglobin

how is bilirubin usually excreted from the body?

it is insoluble in water and so is bound to albumin in blood (=unconjugated)

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transported to and taken up by liver cells where it is conjugated with glucuornic acid (=conjugated/more soluble)

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conjugated bilirubin is excreted via the bile (gut route) or urine (kidney route)

if bilirubin is excreted via bile/gut, what is it called?

stercobilinogen

if bilirubin is excreted via urine/kidney, what is it called?

urobilinogen

what can increased levels of bilirubin result in?

jaundice (yellow discolouration of skin or sclera)

at what level of bilirubin is jaundice detectable?

>50 umol/L (more than double normal level)

what is jaundice most commonly associated with? (3)

- haemolysis (breakdown product of RBCs/haem)

- failed conjugation (prevents excretion)

- biliary obstruction/cholestasis (cannot enter liver/cannot be excreted)

in what sense can haemolysis result in jaundice?

increased haemoglobin breakdown produces excess bilirubin > overloads conjugating capacity

with reference to conjugation status, what is jaundice as a result of haemolysis known as?

unconjugated hyperbilirubinaemia

in what demographic is unconjugated hyperbilirubinaemia (jaundice) common? what effect can this have?

in babies

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it is neurotoxic (can result in brain damage in high levels)

what treatment is associated with high bilirubin in neonates?

phototherapy (blue light therapy to breakdown bilirubin)

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not effective in adults

when would jaundice as a result of failed conjugation occur?

as a result of hepatocellular damage

what is jaundice as a result of failed conjugation also known as? what are the most common causes of this in adults?

acute jaundice

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viral hepatitis and paracetamol poisoning

in addition to elevated bilirubin, what else may be elevated in a LFT as a result of acute jaundice (failed conjugation)? what does this indicate?

AST and ALT

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indicates hepatocellular damage

what does jaundice as a result of biliary obstruction (cholestasis) result from?

gallstones blocking the bile duct

how would an LFT result differ between complete and partial cholestasis?

complete = elevated bilirubin and ALP (and GGT)

partial = normal bilirubin (potentially) with elevated ALP and GGT

how do cholestasis patients usually present? (hallmark sign/symptom) why?

with dark urine

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bilirubin is still becoming conjugated but is not able to pass through bile duct into large intestine so is instead backflowing into blood

which protein is the major protein product of the liver?

albumin

what does low albumin indicate? why?

advanced chronic liver disease

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it has a long half life (~20 days) and so it would take a long time for any significant decrease to occur - therefore if a decrease is apparent, then there must be long-term damage

what is AFP? what level of AFP is expected in a normal adult? when would this differ?

alpha-fetoprotein - more or less the foetal equivalent of albumin (synthesised by foetal liver)

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levels should be low in a normal adult

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levels would be high in liver cancer (hepatocellular carcinoma)

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it is (hence) a maker for germ-cell tumours

what are the three most common causes of acute liver disease?

- poisoning

- infection

- inadequate perfusion (circulation)

which poisoning most commonly affects the liver?

paracetamol

what is the most common cause of acute liver failure in the UK? (hint: not alcohol)

paracetamol overdose

what legislation was brought in that aimed to reduce paracetamol-related liver failure?

a limit to the number of tablets that cand be purchased at any one time

why is paracetamol so harmful to the liver?

it can only be metabolised in small amounts by the liver

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when it is present in high concentrations it gives rise to toxic metabolites

what are the consequences of paracetmol poisoning on the liver? (symptoms and pathphysiology)

often asymptomatic or non-specific symptoms for first 24 hours

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hepatocyte destruction then begins which can progress to acute liver failure

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liver damage occurs at maximum 3-4 days after ingestion

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may also develop encephalopathy, hypoglycaemia, and renal failure

what laboratory investigations can be carried out in the event of paracetamol poisoning?

serum paracetamol (>4 hours post ingestion)

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U+E (to look for renal failure)

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liver function tests (look for ALT)

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plasma glucose (since hypoglycaemia common when hepatocyte destruction)

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arterial blood gases (acidosis can occur at an early stage and is a poor sign)

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prothrombin time (best indicator of the severity of liver failure) (tend to occur in chronic rather than acute)

what treatment is associated with paracetamol poisoning?

N-acetylcysteine (NAC) - most effective if given within 8 hours

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activated charcoal if ingestion was within previous hour

how can patients at risk of liver damage/requiring treatment be identified in paracetamol poisoning?

using the paracetamol treatment graph (plots dose against time since ingestion)

what can both bacteria and viruses give rise to in the liver?

infective hepatitis

what is hepatitis?

inflammation of the liver

what LFTs would be characteristically altered in infection?

aminotransferases (ALT/AST)

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elevated activity

which liver infections are the most common?

viral hepatitis (A/B/C)

what is meant by inadequate perfusion?

poor flow of fluid (into the liver in this context)

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for reference a healthy adult can withstand a loss of 0.5L from circulation of ~5L

what is the consequence of inadequate perfusion? (hint: ... shock)

hypovolaemic shock

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occurs when volume of circulatory system is too depleted to allow adequate circulation to tissues in the body

what are the two major causes of inadequate perfusion?

major trauma with blood loss

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sepsis (BP dropping to dangerously low level as result of infection)

in summary, what are the three main causes of acute liver disease?

poisoning (mainly paracetamol), infection (mainly viral hepatitis), and inadequate perfusion

what are the three potential progressions/outcomes of acute liver disease?

- resolution (majority of cases) (since liver can regenerate)

- progression to acute hepatic failure

- progressio to chronic hepatic damage

in the medical world, what is acute liver failure considered to be? why?

a major medical emergency

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metabolic functions of the liver cannot be compensated for by any other organ

what are the common clinical features of acute liver failure?

jaundice, hepatomegaly (big liver cells)

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renal failure (since kidney exposed to toxins)

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decreased albumin (> hypoalbuminaemia and oedema (which may or may not occur in abdomen))

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decreased clotting factors (> increased risk of haemorrhage)

what recovery/management is associated with acute liver failure?

recovery can take weeks

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monitoring LFTs is useful to assess relapse/prognosis

what are the common causes of chronic liver disease?

alcoholism, hepatitis B/C, autoimmune disease

what pathophysiology does chronic liver disease involve?

auto-antibody production

what can chronic liver disease progress to? what is this?

cirrhosis

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end stage of liver disease (irreversible damage to liver)

what is a common biochemical feature of chronic liver disease?

low albumin

what pathway does ingested alcohol take in the body?

absorbed into bloodstream from stomach and intestines

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passes through liver before circulating around body (highest concentration is in blood flowing through liver)

why is alcoholism associated with chronic liver disease?

liver cells contain enzymes that metabolise alcohol

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they can only process a certain amount per hour

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overwhelming can lead to fatty liver, hepatitis, or cirrhosis (or all occuring at same time)

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may result in liver failure

what is cirrhosis?

end-stage of chronic liver injury

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not reversible, progresses slowly (no early symptoms)

what are the characteristic features of cirrhosis?

extensive liver fibrosis (extensive scar formation)

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jaundice, ascites (fluid in abdomen), and bleeding (in terminal stages)

what can cirrhosis lead to?

end-stage liver disease

how is cirrhosis diagnosed? what contribution can LFTs make?

usually based on symptoms, examination, and history (alcohol)

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LFTs are often normal

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may do blood tests to check for hepatitis or other cause (if not alcohol)

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ultrasound or CT to determine if liver is shrunken/abnormal

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possibly biopsy if cannot be determined

what are the most common causes of cirrhosis in the UK? what else can cause it?

alcohol and Hep C

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can be caused by inherited disease or Hep B

what is haemochromatosis?

an inherited liver disease that can lead to cirrhosis

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most common genetic liver disorder

what does haemochromatosis involve?

it is a disorder of iron absorption that presents later in life

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associated with iron accumulation in liver cells (and pancreas/heart/joints)

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leads to liver fibrosis and risk of hepatocellular carcinoma

what mutation is responsible for haemochromatosis?

mutation in HFE gene

what clinical features are associated with haemochromatosis?

diabetes, cardiac failure, joint involvement (pain etc)

what investigations are associated with haemochromatosis diagnosis?

LFTs, iron indices, biopsy, genetics

what management is associated with haemochromatosis?

venesection (500g whole blood removed weekly until excess iron removed (can take up to 1.5 years) thereafter performed every 3 months indefinitely)

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surveillance for cancer (monitor AFP/do ultrasound)

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screen first degree relatives

what is Wilson's disease? how does it contribute to inherited liver disease?

a rare inherited disorder of copper metabolism

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failure of copper incorporation into its transport protein for excretion in bile >>> accumulation in liver

what symptoms are associated with wilson's disease?

hepatic and neurological damage

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common in young children/young adults

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kayser-fleischer rings in eyes (copper coloured ring around iris, indicates copper build up)

what are some signs and symptoms of wilson's disease?

jaundice, cirrhosis, arthritis, behavioural changes, excessive salivation, kayser-fleischer rings

what may be seen biochemically in wilson's disease?

decrease in total plasma copper (raised free copper)

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decreased caeruloplasmin (copper-carrier)

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increased 24 hour urinary copper

what is required to define the degree of fibrosis in wilson's disease?

a biopsy (would also be required to quantify copper load)

what management is associated with wilson's disease?

penicillamine to chelate copper

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liver transplant if severe

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neurological disease effects are permanent (so coping with these)

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screening first degree relatives

what is hepatocellular carcinoma?

malignant tumour of liver (associated with pre-existing chronic liver disease)

what biochemical signs are associated with hepatocellular carcinoma?

alpha fetoprotein (AFP)

in what patients is the risk of hepatocellular carcinoma increased?

those with primary liver carcinomas

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those with hepatitis and cirrhosis

aside from hepatocellular carcinoma, how else is the liver associated with cancer?

it is a common site of secondary metastases

what tends to be the first indication that cancer is present in the liver?

jaundice (specifically if it is painless)

patient presents with pain in upper right quadrant of abdomen; results were as follows:

high bilirubin

very high AST/ALT

high ALP

high GGT

what is the most likely diagnosis?

increase in AST/ALT indicates acute hepatocellular damage (biggest increase)

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increase in ALP/GGT indicates degree of cholestasis

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most likely diagnosis is acute viral hepatitis (since biggest increase is AST/ALT which is associated with this)

patient presents with painless jaundice; results were as follows:

very high bilirubin

high AST/ALT

very high ALP

very high GGT

what is the most likely diagnosis?

raised ALT/AST indicates hepatocellular damage

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raised ALP/GGT indicates cholestasis

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most likely diagnosis is obstruction of common bile duct (since ALP/GGT are the most raised)

patient with history of cancer presents with the following:

normal bilirubin

normal AST/ALT

very high ALP

normal GGT

what is the most likely diagnosis?

since only ALP is elevated not GGT, suggests increase is not from liver but likely bone

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possibly a metastases to bone from previous cancer? but would need further testing (e.g., a scan)