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Liver disease Flashcards

1
Q

How does the liver metabolise drugs?

A

Phase 1: Either oxidation, reduction or hydrolysis of the drug to add functional chemical groups to make it polar
CYP450 enzymes involved
In smooth endoplasmic reticulum

Phase 2: phase1 products conjugated with endogenous substrates such as glycine, glucuronic acid or sulfuric acid.
Makes them more water soluble and excretable in urine

Phase 3: Excretion (most commonly in kidneys) and can only occur if products are water soluble and small.

If molecule is high polar with a greater molecular weight then its removed via biliary excretion

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2
Q

What drugs can lead to hepatic failure?

A 
 Paracetamol (acetaminophen)
 Antibiotics (ciprofloxacin, erythromycin, isoniazid)
 Antidepressants (amitriptyline)
 Anti-epileptics (phenytoin, valproate)
 Anesthetic agents (halothane)
 Statins 
 Immunosuppressive (cyclophosphamide and methotrexate)
 Salicylates (due to Reye syndrome) 
 NSAIDs

Chronic Alcohol use with some of these drugs causes synergy

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3
Q

What is the effect of acute alcohol consumption on drug metabolism?

A

Acute consumption can have an inhibitory effect of CYP450 so drugs are metabolised slower
Hepatoxicity can occur at lower doses

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4
Q

How can adverse drug reactions be classified?

A 
Type A (Intrinsic/pharmacological):
80% of all hepatotoxicities
These drugs have a predictive dose-response curve and a MOA of toxicity
Rarely dangerous and normally occurs after single dose
Type B (idiosyncratic) 
Rare, non-predictable, toxicity not related to dose and has variable latency time periods 
May be due to reactive metabolites causing a hypersensitivity reaction
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5
Q

How does paracetamol cause hepatotoxicity?

A

Type A adverse reaction (safe in therapeutic doses)
Drug undergo conjugation with glucuronic acid -> water-soluble product BUT large amounts causes saturation some of the drug gets metabloised by CYP450 enzyme
This can form toxic NAPQI and deplete stores of glutathione so the toxic intermediate can no longer be conjugated into safe metabolite

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6
Q

How can alcohol cause hepatitis?

A

Converted to acetaldehyde in the liver via alcohol dehydrogenase in hepatocytes producing reactive oxygen radicals (e.g. HO, hydroxyl, superoxide anion)
NAD converted to NADH causing fatty acid production and steatosis

Radicals can destroy hepatocytes. Acetaldehyde binds to macromolecules and cell membrane to form acetaldehyde adducts (recognised as foreign bodies) causing immune response
Neutrophil infiltration and inflammation.

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7
Q

What histological change occurs in the liver due to alcoholic hepatitis?

A

Mallory bodies form: damaged intermediate filaments within the cytoplasm of hepatocytes. Aggregate together, are highly eosinophilic and appear pink on H&E staining.

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8
Q

Physiology of bilirubin metabolism:

A

Erythocytes go through haemolysis after 2-3 months in spleen -> Unconjugated bilirubin (Biliverdin)
This is fat -soluble and travels to liver via albumin blood plasma proteins and then conjugates with glucuronic acid in liver
Conjugated bilirubin (water soluble now) does not get absorbed by terminal ileum and goes to colon
Here, the healthy commensal deconjugate it to colourless urobilinogen
50% of urobillinogen is reabsorbed and taken up via portal vein to the liver -> kidneys -> oxidised into urobilin -> yellow colour of pee
OR urobilinogen remains in colon and is reduced to Stercobilinogen -> oxidised to stercobilin -> brown colour of poo

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9
Q

What are the investigations for jaundice?

A

 Urine sample (identify presence of bilirubin),
 Haematology FBC (INR, LFTs, prothrombin time and platelet count)
 U&Es, total protein albumin
 Blood culture and liver serology
 Ultrasound (distended ducts, gallstones, pancreatic mass)
 ERCP and MRCP
 Anti-mitochondrial antibody
 Viral markers (HIV, Hep ABC)

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10
Q

What can be the causes for pre-hepatic jaundice?

A 
Increased rate of haemolysis: 
Malaria
Sickle cell
Thalassaemia
Haemolytic Anaemia

Gilbert’s syndrome (lack of conjugation of bilirubin)
Criggler-Najjar syndrome

No bilirubin present in urine but high levels of unconjugated bilirubin in serum

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11
Q

What is Gilbert’s syndrome?

A

genetic disorder where there are elevated levels of unconjugated bilirubin in bloodstream due to UGT1A1 enzyme mutation

Reduced activity of glucoronyltransferase enzyme which is needed for conjugation of billirubin

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12
Q

What are the hepatic causes of jaundice?

A

Liver damage that causes only some of the bilirubin to be conjugated with glucuronic acid

Hepatitis/Hepatotoxicity
Liver Cirrhosis
Alcoholic liver disease
Drugs
Hereditary haemochromatosis (hepcidin) 
Primary sclerosing cholangitis/ primary biliary cirrhosis

Mixture of conjugated and unconjugated bilirubin present. Plasma albumin levels are low.

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13
Q

What are the post-hepatic causes of jaundice?

A

Obstructive jaundice:
Choledocholithiasis
Head pancreatic cancer
biliary-atresia (failure of formation of tubes)
Cholangiocarcinoma (cancer of gallbladder)

Conjugated bilirubin present in urine but no urobilinogen
Pale stools and dark urine (as no conversion to urobilinogen therefore no stercobilin)

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14
Q 
Comment on the levels of following in pre-hepatic jaundice: 
Total bilirubin
Conjugated bilirubin
Unconjugated bilirubin
Urobilinogen
ALP levels
ALT and AST levels
Conjugated bilirubin in urine
Large spleen
A 
TB- Increased 
CB - Normal
UB - Increased
U - Normal
ALP - Normal
ALT/AST - Normal
CB in urine: Not present 
Large spleen
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15
Q 
Comment on the levels of following in hepatic jaundice: 
Total bilirubin
Conjugated bilirubin
Unconjugated bilirubin
Urobilinogen
ALP levels
ALT and AST levels
Conjugated bilirubin in urine
Large spleen
A 
TB- Increased 
CB - Potentially increased
UB - Potentially increased
U - Decreased
ALP - Increased
ALT/AST - Increased
CB in urine: Present
Large spleen
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16
Q 
Comment on the levels of following in post-hepatic jaundice: 
Total bilirubin
Conjugated bilirubin
Unconjugated bilirubin
Urobilinogen
ALP levels
ALT and AST levels
Conjugated bilirubin in urine
Large spleen
A 
TB- Increased 
CB - Increased
UB - Normal
U - Decreased
ALP - Increased
ALT/AST - Increased
CB in urine: Present
Absent Large spleen
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17
Q

What are the main sources of Alkaline Phosphatase?

A

1- Cells of hepatobiliary tract
2- Osteoblasts of bone
3- Intestine and placenta &renal tubules.

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18
Q

What can be used to ascertain whether increased ALP is due to bone or hepatobiliary disease?

A

GGT will be normal in bone diseases

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19
Q

What can cause a clinically significant raised level of ALP?

A

periods of active bone growth in infancy and at puberty
Pregnancy 2nd and 3rd trimesters due to placental ALP
Osteogenic tumours
Paget’s disease of bone
Rickets/osteomalacia
Hyperparathyroidism
Healing of bone fractures
Obstructive jaundice
Cholestasis, cholangitis, gallstones, cholecystitis
Hepatitis

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20
Q

Why does GGT (gamma glutamyl transferase) increase?

A

Present in blood, originates in hepatobiliary system
Causes of increase:
1- Alcohol, drug (anticonvulsants) cause increased secretion of GGT
2- Biliary obstruction (esp obstructive jaundice)
Increases earlier than ALP and persists longer
3- Hepatitis
4- Liver tumours

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21
Q

Causes of increased blood amninotransferases (ALT/AST)

A

1- Hepatitis (in viral ALT is more elevated than AST)
2- Cirrhosis (AST is more elevated in chronic disease)
3- Obstructive jaundice
4- Alcohol or drug intake

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22
Q

What are the causes of AST raise but not ALT?

A

ALT is specific to the liver

ACT increases can be due to:
1- Liver diseases
2- Myocardial infarction (MI)
3- Progressive skeletal muscular dystrophy
4- Crush injury
5- Hemolytic diseases
6- Artifact: in hemolysed samples or if serum separation is delayed.

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23
Q

Caused for decreased serum albumin?

A

Pregnancy
Decreased amino acids: in diet & reduced synthesis of nonessential amino acids due to either Malnutrition or Malabsorption.
Increased catabolism : Surgery, Trauma, Infections.
Defective synthesis in liver: Chronic liver diseases (liver cirrhosis)
Increased loss : From the kidney (Nephrotic syndrome) or From GIT (Protein loosing enteropathies)

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24
Q

Why would prothrombin time be increased in liver disease?

A

liver makes prothrombin and other clotting factors
When the PT is high, it takes longer for the blood to clot
Higher PT means liver damage

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25
Q

What happens to AFP (Alpha fetoprotein) in liver disease?

A

Increases

Can be used to screen and diagnosis hepatocellular carcinoma and hepatoblastoma

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26
Q

What happens to ammonia in liver disease and why?

A

Ammonia is disposed by formation of urea in liver. hyperammonemia occurs in liver disease and can be toxic to CNS

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27
Q

Causes of hyperammonaemia:

A

Liver disease:
Gi bleeding - bacteria in GIT on blood urea with production of ammonia
Ornithine transcarbamoylase deficiency (Hereditary)

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28
Q

How would acute cholecystitis present?

A

Epigastric pain - radiating to the shoulder and in RUQ
Muscle guarding
Positive murphy’s sign (pain present on deep inspiration as well during palpation)
Rebounding tenderness

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29
Q

What is the pathophysiology behind acute cholecystitis

A

Inflammation of gallbladder secondary to obstruction of gallbladder emptying

Obstruction increases gallbladder secretion -> progressive distention -> compromises vascular supply to gallbladder

Bile stasis irritates mucosa -> inflammation and bacterial growth

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30
Q

What is the presentation and pathophysiology behind Acute/ascending cholangitis?

A 
CHARCOT'S TRIAD - Fever, RUQ pain, Jaundice
septic shock (hypotension)

Obstruction of common bile duct (choledocholithiasis) by stones, tumour or trauma leads to this -> biliary stasis and distention

Bacteria can ascend from Ampulla of Vater such as e/coli, klebsiella and enterococcus
Bacteria can enter bloodstream causing sepsis

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31
Q

What is the presentation and pathophysiology behind Primary biliary cholangitis?

A

Middle aged women
Jaundice, Xanthomas (cholesterol accumulation), Pruritus, joint pain and arthropathy, xanthelasmas, xanthomata

Autoimmune disease ANTI-MITOCHONDRIAL ANTIBODIES -> small bile ducts destruction due to granuloma formation -> bile leaks into interstitial space -> inflammation. THIS IS INTRA-HEPATIC ONLY

Smoking increases risk

Complications: cirrhosis, steatorrhoea, malabsorption, sicca syndrome

Treatment: UDCA

32
Q

What is the presentation and pathophysiology behind Primary sclerosing cholangitis?

A

Fatigue, pruritus, jaundice and fever

Autoimmune condition - infiltration of T cells against bile duct epithelium -> INTRA AND EXTRA-HEPATIC loss of biliary tree -> lumen of tree becomes hardened and sclerosed due to scar formation -> strictures due to scarring -> obstruction of bile flow

Associated with IBD, men, smoking reduces risk

33
Q

What is the presentation and pathophysiology behind Cholangiocarcinoma?

A

Abdominal mass, ascites, jaundice, malaise

Cancers that begin in the bile ducts.
Very rare neoplasm (1%) and is an adenocarcinoma. Hyperplasia -> metaplasia -> dysplasia to form cancer.
Chronic inflammation and cancer reduces size of lumen and obstructs bile drainage

34
Q

Increased GGT levels but normal ALP would indicate what?

A

Alcohol abuse

35
Q

What is the definition of acute liver failure and how does it present?

A

Acute liver failure is defined as the rapid development of hepatocellular dysfunction, specifically
coagulopathy and encephalopathy in a patient without known prior liver disease.

Symptoms include:
 Jaundice,
 Hepatic encephalopathy (confusion),
 Asterixis/CO2 flap,
 Nausea and vomiting,
 Spider angiomas, naevi (type of telangiectasia due to damage of arteriole sphincters, as oestrogen cannot be metabolized).
36
Q

What are the main causes for Acute liver failure?

A

Paracetamol/ amphetamine overdose
Idiosyncratic adverse drug reaction
Excessive alcohol consumption
Viral Hepatitis (Hep A or B)

37
Q

In acute amphetamine overdose, toxification mainly occurs in which zone?

A

Zone III due to the highest levels of CYP450 enzymes being found here

38
Q

In the CNS, how are ammonium compounds normally removed?

A

Via astrocytes by converting glutamate to glutamine

In liver failure, the excess glutamine causes an osmotic gradient which encourages water influx -> cerebral oedema and confusion

39
Q

Initial investigations for acute liver failure:

A

 LFTs, prothrombin time and INR,
 U&Es, urea and creatinine,
 FBC, ABGs, blood type and screen,
 Urine toxicity screen (looking for paracetamol),
 Viral hepatitis serologies, autoimmune hepatitis markers,
 Pregnancy test, chest x-ray and abdominal ultrasound.

40
Q

Management of acute liver failure:

A
  • IV fluids, analgesia, nutritional support
  • Raise head to 30*, intubate
  • Liver transplant assessment
  • PPIs as prophylaxis for GI bleeds
  • Monitor neurological status
  • Monitor blood glucose and electrolytes
  • FBC, INR, LFTs, UEs monitorning
  • Treat underlying cause
41
Q

Treatment for paracetamol overdose

A

IV Acetylcysteine

Consider charcoal administration if patient presents within 1 hour of ingestion

42
Q

Treatment for opioid overdose:

A

Naloxone

43
Q

Treatment for autoimmune hepatitis:

A

Benzylpenicillin
Acetylcysteine
Methylprednisolone

44
Q

What is acute-on-chronic liver syndrome?

A 
Acute decompensation of chronic liver
disease associated with organ failure and short-term mortality. 
CIRRHOSIS, ALCOHOIC HEPATITIS AND
CHRONIC VIRAL HEPATITIS ARE THE MOST COMMON UNDERLYING LIVER DISEASES. 
Triggers of
decompensation in ACLF include:
 Bacterial infections,
 Alcohol,
 Acute viral hepatitis
 Drug-induced-liver injury.
45
Q

What are some infective causes of hepatomegaly and the clinical features associated?

A

Presents as: enlarged liver, lymphadenopathy, fever, rigours, malaise. Smooth enlarged liver is suggestive of hepatitis

 Infective mononucleosis (sore throat),
 Viral hepatitis (A, B and C),
 Malaria,
 Amoebic abscesses (single celled organism able of changing shape via pseudopods)
 Hydatid cyst (Echinococcosis parasitic disease of tapeworms),
 Leishmaniasis.

46
Q

What are some neoplastic causes of hepatomegaly and the clinical features associated?

A

Unintentional weight loss, cachexia, anorexia, lymphadenopathy, nausea and vomiting, night sweats. CRAGGY liver edge

 Leukemia (CML and CLL),
 Lymphoma,
 Hepatocellular carcinoma,
 Metastatic tumors.

47
Q

What are some biliary causes of hepatomegaly and the clinical features associated?

A

Visible jaundice, pruritus, fatigue, dry eyes and
dry mouth, pale stools and dark urine.

 Primary biliary cirrhosis (xanthalasma),
 Primary sclerosing cholangitis
 Extra-hepatic obstruction (pancreatic cancer, cholangiocarcinoma),
 Liver cirrhosis (jaundice, spider naevi, palmar erythema, dark urine and pale stools).

48
Q

What are some metabolic causes of hepatomegaly and the clinical features associated?

A

Nausea & vomiting, change in bowel habit, cachexia, mental state changes, severe abdominal pain

 Wilson’s syndrome (accumulation of iron and copper in the liver and brain),
 Haemochromatosis (increased iron stores in hepatocytes, depositing into liver and joints),
 Acute porphyria (accumulation of porphyria heme precursors which are toxic)
 Non-alcoholic fatty liver disease and Amyloid.

49
Q

How would drug induced hepatomegaly present?

A

Nausea, vomiting, pain, fatigue, fevers, history of substance misuse, anorexia

50
Q

What are some congenital causes of hepatomegaly and the clinical features associated?

A

Long-term management of disorder, crisis episodes that worsen over a short time

 Hemolytic anemia,
 Polycystic liver disease,
 Sickle cell disease,
 Thalassemia,
 Cardiac failure.
51
Q

What initial investigations will be done for hepatomegaly?

A

 Physical examination (smooth, tender, craggy),
 Lymphadenopathy,
 FBC, U&Es, LFTs, prothrombin, INR, CRP and blood film
 Full liver screen (viral hepatitis screen, ferritin, alpha-1-antitrypsin, immunoglobulins (AMA))
 AFP (biomarker for hepatocellular carcinoma),
 Abdominal ultrasound,
 Ascitic tap if ascites is present.

52
Q

How is variceal bleeding caused in liver failure?

A

Extensive scarring and fibrosis of liver compresses and narrows lumen of hepatic vessels, reducing blood flow, causing portal hypertension -> congestion of blood -> this passes into collateral circulation such as veins of lower oesophagus -> these veins get dilated and more prominent -> get damaged and rupture when coughing/eating

People with variceal often present with haematemesis and upper GI bleeding
Treatment: vasopressin, beta-blocker or surgical

53
Q

What is the physiology behind hepato-renal syndrome?

A

Sudden insult to liver (infection or GI bleed)
-> during liver cirrhosis, release of NO, prostaglandins and other vasoactive substances -> cause splanchnic vasodilation -> hypotension in kidneys -> RAAS activation -> vasoconstriction -> further hypoperfusion in kidneys

Fatal condition with medial survival of 2 weeks. Dialysis and liver transplant required

54
Q

What is the physiology behind ascites?

A
  1. portal hypertension -> splanchnic dilation -> hypoperfusion -> RAAS activation -> Sodium reabsortion by angiotensin II + ADH release +aldosterone release -> fluid retention
  2. Decrease in liver function means less albumin -> osmotic pressure in vessels in reduced -> encourages extravasation

Complications: bacterial peritonitis, hepato-renal syndrome, thrombosis

55
Q

What are the investigations for ascites?

A

History: cirrhosis, malignancy, heart failure or TB
Examination: Shifting dullness in abdo
FBC (platelets and anaemia), LFTs, U&Es, INR, prothrimbin, ABG
Abdo ultrasound
Chest x-ray (pleural effusion or heart failure)
Ascitic tap (20ml drained for diagnostic paracentesis)

56
Q

How is hepatic ascites managed?

A

Spironolactone
Furosemide
(aim for weight loss of 1kg/daily initially)

Therapeutic paracentesis/drain
Human albumin solution given with large-volume paracentesis (>5L)

Trans-jugular intrahepatic portosystemic shunts - used if frequent paracentesis is needed

57
Q

Risk factors for chronic liver disease?

A

 Excessive alcohol consumption,
 Hepatitis B and C (unprotected sex, healthcare professionals, sharing infected needles),
 Obesity,
 Metabolic syndrome (obesity, hypertension, diabetes, hypertriglyceridemia & hyperlipidemia).
 Certain medications (paracetamol, amitriptyline, statins and NSAIDs).

58
Q

Why is INR useful?

A

Best marker of liver function

59
Q

ceruloplasmin

A

Copper carrying protein tested for when suspecting Wilson’s disease

60
Q

Hepatic encephalopathy treatment

A

Lactulose

Electrolytes

61
Q

What is the transfer criteria to specialised units for patients with acute liver failure?

A

INR >3.0
•Presence of hepatic encephalopathy
•Hypotension after resuscitation with fluid
•Metabolic acidosis
•Prothrombin time (seconds) > interval (hours) from overdose (paracetamol cases

62
Q

What is Autoimmune hepatitis:

A

Liver damage by CD4+ T cells
Presentations at peri and post menopausal group- Asymptomatic or fatigue and chronic liver disease
In teens presents as acute liver failure
Patients have other autoimmune disease

63
Q

What antibodies have been recognised in Autoimmune hepatitis?

A

Type 1 - ANA and anti-smooth muscle (anti-actin)

Type 2 - anti-liver/kidney microsomal (Anti- LKM1)
Main target is CYP2D6

64
Q

What blood results will be seen in a patient with haemochromatosis?

A

Raised transferrin saturation - due to increased iron causing increased transferrin binding
Raised ferritin
Low TIBC - most sites taken up by the increased iron

65
Q

What is haemochromatosis?

A

Autosomal recessive disorder of iron absorption and metabolism = iron accumulation
HFE gene mutation disrupting hepcidin synthesis

66
Q

What are the sources of Hepatitis E in the UK?

A

Contaminated pork/sausage

Water in endemic areas

67
Q

What is Alagille syndrome?

A

Genetic disorder where there is liver damage dye to abnormalities in bile duct. Multisystem disease so also effects heart, brain, eyes, face and skeleton

Most diagnosed by age 5

68
Q

What syndrome presents with sudden onset abdominal pain, ascites and tender hepatomegaly?

A

Budd-Chiari syndrome

hepatic vein thrombosis

69
Q

Having primary sclerosing cholangitis puts you at risk of developing what cancer?

A

Cholangiocarcinoma in 10% of patients with PSC

70
Q

1) What is the most common cause of hepatocellular carcinoma in the UK?
2) And worldwide?

A

1) Hepatitis C

2) Hep B

71
Q

What is the biggest risk factor for developing HCC?

A

Liver cirrhosis secondary to Hep B/C, alcohol, haemochromotosis, primary biliary cirrhosis

72
Q

How can we screen for HCC in high risk groups (e.g. liver cirrhosis pts)

A

Ultrasound with alpha fetoprotein

73
Q

The oral contraceptive pill is associated with which jaundice causing diagnosis?

A

Drug-induced cholestasis

74
Q

The combination of deranged LFTs combined with secondary amenorrhoea in a young female strongly suggest what diagnosis?

A

Autoimmune hepatitis

75
Q

What is the treatment for alcoholic hepatitis?

A

Corticosteroids

Liver transplant

GI (10 decks)

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