Hepatobiliary

Question 1

What is Acute liver failure (ALF)

Answer 1

Acute liver failure is a syndrome of acute liver dysfunction without underlying chronic liver disease.

ALF is characterised by coagulopathy (derangement in clotting) of hepatic origin and altered levels of consciousness due to hepatic encephalopathy (HE).

ALF can be divided into hyperacute, acute and subacute based on the speed at which HE develops:

• Hyperacute: HE within 7 days of noticing jaundice. Best prognosis as much better chance of survival and spontaneous recovery.
• Acute: HE within 8-28 days of noticing jaundice
• Subacute: HE within 5-12 weeks of noticing jaundice (ALF may be defined up to 28 weeks). Worst prognosis as usually associated with shrunken liver and limited chance of recovery.

HE occurring more than 28 weeks after onset of jaundice is categorised as chronic liver disease. Usually presenting with decompensated chronic liver disease (dCLD) or acute on chronic liver failure (ACLF) depending on the severity of illness.

Acute-on-chronic = liver failure as a result of decompensation of chronic liver disease.

Fulminant hepatic failure = clinical syndrome resulting from massive necrosis of liver cells leading to severe impairment of liver function. Sudden onset.

Question 2

Epidemiology of ALF

Answer 2

ALF is the primary indication for liver transplantation in around 8% of cases within Europe.

Question 3

Aetiology of ALF

Answer 3

• Acute liver injury (ALI): severe acute liver injury from a primary liver aetiology. Characterised by impaired liver function but hepatic encephalopathy is absent, unlike in ALF.
  
  • Viral (Hepatitis A, B and CMV) - most common worldwide
  • Other infections e.g. yellow fever, leptospirosis, EBV
  • Drug-induced liver injury - paracetamol and non-paracetamol (e.g. alcohol, anti-depressants, NSAIDs, ecstasy/cocaine, antibiotics). Most common cause across Europe
  • Toxin-induced(e.g. Amanita phalloides - death cap mushroom that contains amatoxins andphallotoxins, carbon tetrachloride)
  • Budd-chiari syndrome and vascular occlusive disease
  • Pregnancy-related(e.g. fatty liver of pregnancy, HELLP syndrome)
  • Autoimmune hepatitis
  • Wilson’s disease
• Secondary liver injury (SLI): similar to ALI but no evidence of a primary liver insult.
  
  • Ischaemic hepatitis
  • Liver resection(post-hepatectomy liver failure)
  • Severe infection(e.g. malaria)
  • Malignancy infiltration(e.g. lymphoma)
  • Heat stroke
  • Haemophagocytic syndromes - immune disease characterised by cytokine storm and overwhelming inflammation

Question 4

Patho of ALF

Answer 4

The exact pathophysiology of ALF depends on the underlying aetiology leading to liver dysfunction. Most cases of ALF are associated with a direct insult to the liver leading tomassive hepatocyte necrosisand/orapoptosis(programmed cell death), which prevents the liver from carrying out its normal function.

As the condition progresses it can lead to ahyperdynamic circulatory statewith low systemic vascular resistance due to a profound inflammatory response. Collectively, this causes poor peripheral perfusion and multi-organ failure. Patients also develop significantmetabolic derangements(e.g. hypoglycaemia, electrolyte derangement) and are atincreased risk of infection.

Marked cerebral oedema occurs, which is a major cause of morbidity and mortality in ALF. This is thought to be due to hyperammonaemia (as liver fails to clear ammonia) causing cytotoxic oedema and increased cerebral blood flow that disrupts cerebral autoregulation.

Question 5

Signs and symptoms of ALF

Answer 5

Hepatic encephalopathy

• Altered mental status
• Confusion
• Apraxia - difficulty with motor planning
• Asterixis: flapping tremor suggestive of HE
• Raised intracranial pressure: papilloedema, bradycardia, hypertension, low GCS
• Fetor hepaticus - smell of pear drops, suggests liver isn’t able to clear toxins properly
• Jaundice
• Right upper quadrant pain(variable)
• Hepatomegaly
• Ascites
• Bruising(coagulopathy)
• GI bleeding: haematemesis, melaena
• Hypotension and tachycardia: reduce systemic vascular resistance and hyperdynamic circulation
• Signs of chronic liver disease: signifies acute-on-chronic

Question 6

Grading of hepatic encephlopathy

Answer 6

The severity of HE can be graded using theWest Haven criteria:

• Grade I: change in behaviour with minimal change in level of consciousness. May have mild asterixis or tremor.
• Grade II: gross disorientation, drowsiness, asterixis and inappropriate behaviour
• Grade III: marked confusion, incoherent speech, sleeping most of the time but rousable to verbal stimuli. Asterixis less noticeable, elements of rigidity.
• Grade IV: coma that is unresponsive to verbal or painful stimuli. Evidence of decorticate or decerebrate posturing.

Question 7

Investigations for ALF

Answer 7

• Bloods - for diagnosis and severity
  
  • Full blood count - infection, GI bleed, low MCV?
  • Urea & electrolytes - low urea, high creatinine (hepatorenal syndrome)
  • Liver function tests - including transaminitis (i.e. deranged liver function tests ALT/AST), hyperbilirubinaemia, prolonged prothrombin time, low albumin
  • Blood glucose - low glucose as liver is a glucose store
  • Arterial ammonia - raised ammonia levels
  • Arterial blood gas(pH and lactate) - shows metabolic acidosis
  • Coagulation - urgent INR
  • Lactate dehydrogenase - elevated
  • Lipase/amylase: pancreatitis complication of ALF
  • Blood cultures: sepsis is major cause of morbidity and mortality
• Non-invasive liver screen - to determine aetiology
  
  • Paracetamol serum level
  • Alpha-1 antitrypsin levels
  • Caeruloplasmin levels
  • Ferritin levels
  • Autoimmune markers: ANA, autoantibodies, immunoglobulins, ANCA
  • Toxicology screen: serum/urine
  • Ascitic tap
  • Viral screen: blood and urine culture
    
    • Hepatitis A: anti-HAV IgM
    • Hepatitis B: HBsAg, anti-HBc IgM +/- HBV DNA levels
    • Hepatitis C: anti-HCV (unlikely to cause ALF - may be co-infected)
    • Hepatitis D: if positive for HBV
    • Hepatitis E: anti-HEV IgM +/- HEV RNA levels
    • Other: CMV, EBV, HSV, VZV, Parvovirus
• Imaging -
  
  • Ultrasound - to see liver size and underlying liver pathology
  • Doppler ultrasound - to assess patency of hepatic and portal veins
  • Chest x-ray
  • CT abdomen and pelvis - examine liver architecture, volume, vascular integrity etc
• Other
  
  • EEG - to assess hepatic encephalopathy
  • Assess arterial ammonia - to assess hepatic encephalopathy

Question 8

Management of ALF

Answer 8

• Treat underlying cause
• Good nutrition - thiamine and folate supplementation
• Management based on organ system
  
  • Cardiovascular: fluid resuscitation +/- use of inotropic agents (increase vascular tone and contractility)
  • Respiratory: intubation and ventilation may be needed forHE or respiratory failure.Consider paracentesis to improve oxygenation. Chest physiotherapy. Extracorporeal membrane oxygenation (ECMO) may be needed in selected patients.
  • Gastrointestinal: nutrition (NG feeding +/- total parenteral nutrition), gastric ulcer prophylaxis (proton pump inhibitor), and assess for pancreatitis. Manage GI bleeding as needed.
  • Metabolic:
    
    • Hypoglycaemia: maintain blood glucose level 8-11 mmol/L
    • Hyponatraemia: maintain serum sodium 140-145 mmol/L. May require hypertonic saline, improves intracerebral pressure.
    • Acidosis and lactate: used as part of transplant selection criteria
    • Hypophosphataemia: suggestive of liver regeneration, good prognostic sign. Needs correction.
  • Renal: acute kidney injury is common. May require renal replacement therapy - haemofiltration or haemodialysis
  • Coagulopathy: imbalance in coagulation (loss of pro and anticoagulation factors withlow platelets). No increased bleeding risk. Use Vit K, platelets, blood products or frozen fresh plasma if bleeding.
  • Sepsis: high risk of life-threatening infections including fungal. Early, aggressive treatment of infections with broad spectrum anti-microbials.
  • Neurological: may require intubation and ventilation for high grade HE due to risk of aspiration. Treat seizures with phenytoin. Also at risk of raised intracranial pressure (ICP). Need specific raised ICP monitoring and management e.g. **IV Mannitol
  • Liver: should be assessed and considered for urgenttransplantation

Question 9

Monitoring for ALF

Answer 9

Fluids - urinary and central venous cannulas

Bloods - daily FBC, U&E, LFT and INR

Glucose - 1-4hr + administer IV glucose if needed

Question 10

Complications of ALF

Answer 10

Major complications associated with ALF include sepsis due to marked immune dysfunction and progressive multi-organ failure. This includes:

• Acute kidney injury/ hepatorenal syndrome
• Metabolic disturbance
• Hypoglycaemia
• Haemorrhage (e.g. GI Bleeding)
• Cerebral dysfunction (e.g. seizures, irreversible brain injury).
• Patients are at risk of high output cardiac failure due to low vascular resistance from the widespread inflammatory response.
• Sepsis

Question 11

Prognosis for ALF

Answer 11

Survival from ALF is greater than 60% and around 55% of patients will have spontaneous recovery without need for liver transplantation.

The overall one year survival following emergency liver transplantation is around 80%.

Worst prognosis if grade III-IV encephalopathy, age >40 years, low albumin, high INR, DILI. Late onset hepatic failure worse than fulminant failure.

Question 12

What is the physiological role of the liver

Answer 12

• Storage(i.e. glycogen, iron, vitamins)
• Breakdown(i.e. drugs, toxins, ammonia, bilirubin)
• Synthesis(i.e. bile, cholesterol, coagulation factors, growth factors)
• Immune function(i.e. innate immune protein production, resident immune cells)

Question 13

Define chronic liver disease

Answer 13

Chronic liver disease is caused by repeated insults to the liver, which can result in inflammation, fibrosis and ultimately cirrhosis.

CLD is generally defined as progressive liver dysfunction for six months or longer. The end result of chronic liver disease is cirrhosis, which describes irreversible liver remodelling.

Question 14

Epidemiology of CLD

Answer 14

• CLD represents the fourth commonest cause of years of life lost in those aged under 75.
• In England and Wales an estimated 600,000 patients have CLD.

Question 15

Aetiology of CLD

Answer 15

• Alcohol
• Viral(Hepatitis B, C)
• Inherited(Alpha-1-antitrypsin deficiency, Wilson’s disease, Hereditary haemochromatosis)
• Metabolic(Non-alcohol fatty liver disease / Non-alcoholic steatohepatitis)
• Autoimmune(Autoimmune hepatitis)
• Biliary(Primary biliary cholangitis, primary sclerosing cholangitis)
• Vascular(Ischaemic hepatitis, Budd-Chiari syndrome, congestive hepatopathy)
• Medication(Drug-induced liver injury)
• Cryptogenic(no known cause)

Question 16

Patho of LCD

Answer 16

Overtime, progressive insults to the liver leads toinflammation (hepatitis), fatty deposits (steatosis) and scarring (fibrosis). The normal liver architecture is replaced by fibrotic tissue and regenerative nodules.

The end result of this process is cirrhosis, which describesirreversible liver remodellingthat is associated with significant morbidity and mortality.

• Compensated:Compensated cirrhosis is typically asymptomatic as the liver continues to carry out normal function despite extensive damage.
• Decompensated:On the contrary, decompensated cirrhosis leads to multiple complications due to inadequate liver function:
  
  • Coagulopathy(reducing clotting factor synthesis)
  • Jaundice(impaired breakdown of bilirubin)
  • Encephalopathy(poor detoxification of harmful substances)
  • Ascites(poor albumin synthesis and increased portal pressure due to scarring)
  • Gastrointestinal bleeding(increase portal pressure causing varices)

Question 17

Early manifestation of CLD

Answer 17

Non-specific signs:

Anorexia, lethargy, weight loss, hepatomegaly, nausea or disturbed sleep pattern.

Question 18

Signs and symptoms of CLD

Answer 18

• Caput medusa:distended and engorged superficial epigastric veins around the umbilicus.
• Splenomegaly: enlarged spleen.
• Palmar erythema: red discolouration on the palm of the hand.
• Dupuytren’s contracture:**thickening of the palmar fascia. Causes painless fixed flexion of fingers at the MCP joints (most commonly ring finger).
• Leuconychia:**appearance of white lines or dots in the nails. Sign of hypoalbuminaemia.
• Gynaecomastia: development of breast tissue in males. Reduced hepatic clearance of androgens leads to peripheral conversion to oestrogen.
• Spider naevi: type of dilated blood vessel (i.e. telangiectasia) with central red papule and fine red lines extending radially. Due to excess oestrogen.

Question 19

Signs of decompensated liver

Answer 19

• Encephalopathy:confusion, often present with a flapping tremor (asterixis)
• Ascites:fluid within the peritoneal cavity
• Jaundice:yellow pigmentation of skin and sclera
• GI bleeding: variceal bleeding or slow oozing from portal hypertensive gastropathy
• Coagulopathy: may see marked bruising due to raised INR

Question 20

All investigations for CLD

Answer 20

• Biochemical testing:LFTs - Raised AST and ALTFBCs - thrombocytopenia (indicative of portal hypertension and hypersplenism).Hyperbilirubinaemia, raised INR, low albumin - in decompensated liver disease.
• Transient elastography - assess liver stiffness and fibrosis/ cirrrhosis.
• Imaging
  
  • USS:US is quick, inexpensive, and has a sensitivity of 65-95% for detection of CLD.
  • CT:Provides a more detailed view of the abdominal viscera and is good for secondary findings (e.g. features of portal hypertension).
  • MRI:Is emerging as a highly sensitive and specific modality for liver fibrosis.
• Liver biopsy - can be performed percutaneously using US or CT-guidance, or transjugular.
• Gold standard
  
  • Liver biopsy - invasive so usually reserved for specific cases:
    
    • Liver disease of unknown aetiology
    • Differentiating between acute and chronic disease
    • Unable to differentiate between fibrosis and cirrhosis
• OtherNon-invasive liver screen - due to the wide number of pathologies a ‘non-invasive liver screen’ is often used to determine the aetiology.

Question 21

Management of CLD

Answer 21

• Treat underlying pathology e.g. alcohol cessation, removal of offending medications or use of anti-viral therapies in chronic hepatitis.
• Transplantation based on patient’s ‘United Kingdom model for end-stage liver disease’ (UKELD) score
• Hepatic encephalopathy - caused by liver’s inability to clear harmful substances produced by bacteria in GI tract. Constipation is the main driver of HE.
  
  • First line treatments:Involves laxatives (i.e. lactulose 15-20 mls QDS)to maintain bowel motions.
  • Second-line treatments:Involves the long-term use of antibiotics (i.e. rifaximin).
• Ascites - develops due to a combination of portal hypertension and loss of oncotic pressure (hypoalbuminaemia).
  
  • Aldosterone antagonists:e.g. spironolactone (can be combined with loop diuretics i.e. furosemide).
  • Paracentesis:percutaneous drainage of ascites
• GI bleeding - due to oesophageal varices secondary to portal hypertension
  
  • Beta blockers to reduce portal hypertension
  • Endoscopic variceal band ligation - for variceal haemorrhage
• Spontaneous bacterial peritonitis - infection within the ascitic fluid
  
  • Antibiotics
  • Human albumin solution - draws fluid out peritoneum. Helps to prevent acute kidney injury and hepatorenal syndrome.

Question 22

Monitoring of CLD

Answer 22

• Hepatocellular Carcinoma -
  
  • Six monthly surveillance with ultrasound +/- AFP (tumour marker) as patients with cirrhosis are at high risk of HCC

Question 23

Complications of CLD

Answer 23

• Hepatic encephalopathy
• Ascites
• Gastrointestinal bleeding(i.e. variceal bleed)
• Bacterial infections(i.e. SBP)
• Acute kidney injury
• Hepatorenal syndrome
• Hepatopulmonary syndrome
• Hepatocellular carcinoma
• Acute-on-chronic liver failure

Question 24

Explain Bilirubin metabolism

Answer 24

• Red blood cells are broken down, releasing haemoglobin.
• Haemoglobin is broken down into haem and globin, with haem being further broken down into unconjugated bilirubin and iron. Globin and iron from haem is recycled for erythropoiesis.
• Unconjugated bilirubin is abreakdown product of haemfrom senescent red blood cells
• Unconjugated bilirubin isnot water-solubleand requiresconjugationfor excretion in bile
• UGT (UDP-glucuronosyltransferase)in the liver converts unconjugated bilirubin into conjugated bilirubin, making it water-soluble
  
  • Conjugation involves the addition of glucuronic acid to bilirubin
• Conjugated bilirubin is secreted into the bile canaliculi andstored in the gallbladderas a component of bile
• When it is released into the intestinal tract, conjugated bilirubin is broken down intourobilinogenand thenstercobilinby bacteria
• Stercobilin is excreted infaeces, giving it a brown colour
• Some urobilinogen is reabsorbed and is either directed back into making bile (enterohepatic circulation) or transported to the kidney and excreted in theurine, giving it a yellow colour

Question 25

Explain gallbladder anatomy and physiology

Answer 25

The gallbladder is a small organ with a capacity, in an adult, of about 50ml.

A diverticulum, the gallbladder is continuous with the cystic duct and thus common hepatic duct. It measures between 7-10 cm in an adult. It receives a blood supply from the cystic artery. This vessel has variable origin but most commonly arises from the right hepatic artery.

Note:Hartmanns pouch refers to dilatation or outpouching at the neck of the gallbladder. Stones may impact here causing extrinsic compression of the extrahepatic bile duct leading to Mirrizi’s syndrome.

The biliary tree is a ductal system that transmits bile produced by hepatocytes to the second part of the duodenum (via the ampulla of Vater). By convention it is divided into intrahepatic and extrahepatic ducts.

The right and left hepatic duct converge to form the common hepatic duct. The gallbladder meanwhile is drained by the cystic duct. The cystic duct and common hepatic duct converge to form the common bile duct. The common bile duct forms a common channel with the pancreatic duct just proximal to the ampulla of Vater. The ampulla of Vater is an orifice that allows bile to drain into the second part of the duodenum.

Question 26

Define Cholelithiasis

Answer 26

Cholelithiasis (gallstones) refers to the development of a solid deposit or ‘stone’ within the gallbladder.

Question 27

Epidemiology of gallstones

Answer 27

• Gallstones affect up to 20% of the population.
• F>M
• Prevalence increases with age, before levelling off in the sixth - seventh decade of life.
• More common in caucasians, Native American’s and Hispanics.
• The vast majority of people with gallstones will remain asymptomatic (80%).

Question 28

Aetiology and gall stone composition

Answer 28

Bile is secreted by hepatocytes into the biliary circulation. It is stored in the gallbladder. Bile is composed of bile acids (or salts), phospholipid, bilirubin, cholesterol and water. Imbalance in composition and stasis leads to stone formation.

• Cholesterol stonesCholesterol stones are the most common type found in western populations, estimated to account for up to 75-85% stones. They occur due to crystallisationof cholesterol in bile (along with other compounds) due to supersaturation of cholesterol and crystillisation promoting factors. Disturbances in gallbladder motility may also contribute.
• Black pigment stonesThese are dark stones composed primarilyof calcium bilirubinate, accounting for around 10-20% of stones.They occur in people with increased amounts of bilirubin in their bile -hyperbilirubinbilia. This occurs in patients with increased haemolysis (i.e. haemolytic anaemias).
• Brown pigment stonesThese stones are a mix ofcalcium bilirubinate and a calcium salts of fatty acids, accounting for around 5% of stones.They mostly occur in association with infection (bacterial or parasitic) and may develop de novo in the bile duct after cholecystectomy.

Question 29

RF for gallstones

Answer 29

The classic risk factors for gallstone disease are described as the ‘4 F’s’:

• Female: 2-3 times more likely to develop gallstones than men
• Fat: a BMI > 30 is a key risk factor
• Forties: the risk increases significantly from approximately 40 years old
• Fertile: pregnancy is an important risk factor

Other risk factors:

• Genetic predisposition/ family history
• Rapid weight loss / prolonged fasting
• Diabetes
• Medications- particularly the combined oral contraceptive pill and hormone replacement therapy due to the presence of oestrogen; fibrates also increase the risk
• Crohn’s disease - bile acid malabsorption due to a diseased or resected ileum leads to cholesterol supersaturated bile
• Haemolytic conditions: haemolysis (e.g. sickle cell disease) causes excess circulating bilirubin resulting in pigment gallstones
• Diet(high intriglycerides, refinedcarbohydrates)

Risk factors for becoming symptomatic:

• Smoking
• Parity

Question 30

Clinical manifestations and complications of gallstones

Answer 30

Gallstones are normally asymptomatic. However in a proportion of patients they may cause pathology. A range of conditions may be caused:

• Biliary Colic:This is an acute, severe, RUQ/epigastric pain that tends to be self-limiting. It is the most common complication of gallstones.
• Acute cholecystitis:Impaction of a stone within the cystic duct leads to acute cholecystitis, inflammation of the gallbladder. It presents with signs of infection, RUQ pain and tenderness.
• Acute cholangitisGallstones are the most common cause of acute cholangitis.**Impaction of a stone in the common bile duct impairs drainage leading to infection affecting the biliary tree. Results in ‘Charcot’s triad’ (rightupperquadrantpain,feverandjaundice)
• Acute pancreatitis:Gallstones are the most common cause of pancreatitis in the UK, they occur when stones get impacted distally in the biliopancreatic duct causing disruption to flow of pancreatic enzymes.
• Mucocoele/empyema: obstructed gallbladder fills with mucus/pus.
• Mirizzi’s Syndrome: Stone in gallbladder presses on bile duct, causing jaundice.
• Obstructive jaundice: due to**a stone that obstructs the common bile duct; presents with jaundice, pale stools and dark urine
• Gallstone ileus: stone erodes through the gallbladder into the duodenum and may obstruct the ileum
• Gallbladder cancer: gallstones are thought to increase the risk by up to 5-fold

Question 31

Summary of investigations and management of gallstones

Answer 31

Biliary colic:
Symptoms - intermittent, self limiting RUQ pain
Observations - normal
Examination - normal or mild tenderness
Blood tests - Normal
Ultrasound - gallstones

Acute cholecystitis:
Symptoms - RUQ pain, fevers, malaise
Observations - Fever, Haemodynamic instability may occur
Exam - Tenderness, maybe localised guarding
Blood test - Rised WCC/CRP, Normal/mild LFT increase
Ultrasound - Gallstones, inflamed thickened GB, pericholecystic fluid

Acute cholangitis:
Symptoms - RUQ pain, fevers, malaise, confusion
Observations - fevers, haemodynamic instability more likely to occur
Exam - Tenderness, clinical jaundice may be apparent
Blood tests - Raised WCC/CRP, Raised bilirubin, ALP, ALT
Ultrasound - CBD stone, duct dilation

Acute pancreatitis:
Symptoms - Epigastric pain, radiates to back
Observations - fever and tachycardia
Exam - Epigastric tenderness
Blood test - raised amylase, WCC, CRP normally raised
Ultrasound - Not imaging of choice, may show gallstone

Question 32

Prognosis for gallstones

Answer 32

The majority of patients with gallstones will be asymptomatic. 1-4% of patients develop gallstone-related complications, the most common being biliary colic. 10-20% of those who have had an attack of biliary colic will go on to develop a more serious complication, such as acute cholecystitis

Question 33

Define biliary colic

Answer 33

Biliary colic refers to a pain in the RUQ/epigastrium caused by gallstones.

Though termed a ‘colic’ the pain is normally constant lasting from 30 minutes to 6 hours.

Question 34

Epidemiology of biliary colic

Answer 34

• It is the most common symptomatic manifestation of cholelithiasis (gallstones) affecting around 10-20% of patients.
• Prevalence increases with age
• F>M
• More common in caucasians, Native American’s and Hispanics.

Question 35

RF for biliary colic

Answer 35

Risk factors of cholelithiasis:

The classic risk factors for gallstone disease are described as the ‘4 F’s’:

• Female: 2-3 times more likely to develop gallstones than men
• Fat: a BMI > 30 is a key risk factor
• Forties: the risk increases significantly from approximately 40 years old
• Fertile: pregnancy is an important risk factor

Other risk factors:

• Genetic predisposition/ family history
• Rapid weight loss / prolonged fasting
• Diabetes
• Medications- particularly the combined oral contraceptive pill and hormone replacement therapy due to the presence of oestrogen; fibrates also increase the risk
• Crohn’s disease - bile acid malabsorption due to a diseased or resected ileum leads to cholesterol supersaturated bile
• Haemolytic conditions: haemolysis (e.g. sickle cell disease) causes excess circulating bilirubin resulting in pigment gallstones
• Diet(high intriglycerides, refinedcarbohydrates)

Question 36

Pathophysiology of biliary colic

Answer 36

The pain occurs when a stone impacts against the cystic duct during contraction of the gallbladder with increased pressures in the gallbladder itself.

Question 37

Clinical manifestations of biliary colic

Answer 37

• Nausea and vomiting
• Right upper quadrant pain
• Epigastric pain
• Pain may radiate to right shoulder or interscapular region

Episodes typically last 30 minutes - 6 hours. Often worse after ingestion of fatty foods.

Note: there are no signs on abdominal examination. Murphy’s sign negative.

Question 38

Investigations of biliary colic

Answer 38

• 1st lineAbdominal ultrasound - can identify gallstones as well as looking for dilation of the CBD and presence of stones in CBD.LFTs - may show derangement of LFTs - indicative of stones within the biliary system (which can be asymptomatic). It is essential to identify patients with CBD stones prior to any cholecystectomy.
• OtherMany other investigations may be ordered depending on the presentation and co-morbidities. Alternative diagnoses should be considered and appropriately investigated.
  • FBC and CRP: neutrophilia and raised CRP may suggest cholecystitis
  • Amylase level: if suspecting pancreatitis secondary to suspected gallstone disease
  • Magnetic resonance cholangiopancreatography (MRCP): if no common bile duct stones are seen on abdominal ultrasound, but:
    
    • Thecommon bile duct is dilatedon abdominal ultrasoundand/or
    • Liver function testsare abnormal
  • Endoscopic ultrasound (EUS): if MRCP does not allow a diagnosis to be made

Question 39

Differentials for biliary colic

Answer 39

• Cholecystitis
• Ascending cholangitis
• Common bile duct stone
• Gastritis
• Peptic ulcer disease
• IBS
• Carcinoma on right side of colon
• Renal colic
• Pancreatitis

Question 40

Management for biliary colic

Answer 40

• Analgesia:Simple pain relief with paracetamol and NSAIDs (in the absence of contra-indications). Occasionally opioid analgesia may be required in cases of severe pain.
• Diet:A low-fat diet may be trialled with some patients
• Surgical management
  
  • Prior to cholecystectomy it is key that CBD stones are excluded: ultrasound and LFTs. If CBD is suspected, there are two options:
    
    • MRCP +/- ERCP:MRCP allows for confirmation of stones in the biliary tree. If present ERCP allows for therapeutic intervention with stone retrieval, sphincterotomy and stent placement prior tocholecystectomy.
    • On-table cholangiogram:Less commonly available and technically challenging. During the laparoscopiccholecystectomy the bile duct is intubatedto allow the injection of dye with fluoroscopy in-theatre to diagnose stones in the biliary tree. Various techniques may then be used to retrieve/expel stones.
  • Elective laparoscopic cholecystectomy

Question 41

Complications of biliary colic

Answer 41

• Obstructive jaundice:due to**a stone that obstructs the common bile duct; presents with jaundice, pale stools and dark urine
• Cholecystitis:inflammation of the gallbladder results infever,rightupperquadrantpain(usually > 6 hours) and positiveMurphy’s sign
• Ascending cholangitis:infection of the biliary tree results in ‘Charcot’s triad’ (rightupperquadrantpain,feverandjaundice)
• Acute pancreatitis:gallstones are the most common cause
• Gallbladder empyema
• Gallstone ileus:a rare form of small bowel obstruction due to impaction of a gallstone within the lumen of the small intestine via a cholecysto-duodenal fistula
• Gallbladder cancer: gallstones are thought to increase the risk by up to 5-fold

Question 42

Define acute cholecystitis

Answer 42

Acute cholecystitis refers to inflammation of the gallbladder most commonly occurring due to impacted gallstones (calculous cholecystitis)

Relatively rarely acute cholecystitis occurs in the absence of gallstones (acalculous cholecystitis)

Question 43

Epidemiology of acute cholecystitis

Answer 43

Acute cholecystitis occurs in 10% of patients with symptomatic gallstones

Question 44

Pathophysiology of Acute Cholecystitis

Answer 44

The initial event is the obstruction of gallbladder emptying.

Obstruction results in an increase of gall bladder glandular secretion leading to progressive distension that, in turn, may compromise the vascular supply to the gall bladder. There is also an inflammatory response (this differentiates acute cholecystitis from biliary colic) secondary to retained bile within the gallbladder - infection is a secondary phenomenon following vascular and inflammatory events.

• Acute calculous cholecystitisInflammation and infection occur when a stone becomes impacted in the cystic duct.The exact pathogenesis is still not understood and it is thought the presence of additional mediators is required for cholecystitis to occur. An impacted stone leads to impaired drainage of gallbladder contents and the release of inflammatory mediators. This leads to bacterial overgrowth, usually involving gram-negative rods or anaerobes.Though patients with acute cholecystitis are always treated with antibiotics it is thought that a significant proportion of patients have a sterile inflammation.
• Acute acalculous cholecystitisAcute acalculous cholecystitis refers to gallbladder inflammation in the absence of gallstones.Acalculous cholecystitis is far less common than calculous cholecystitis and is normally seen in patients with significant systemic upset or following major surgery. Risk factors include:
  • Diabetes
  • Age
  • Recent major surgery(e.g. Cardiac surgery)
  • Myocardial infarction
  • Sepsis
  • Major burn
  • Major trauma
  • Cancer
  • Cryptosporidium or cytomegalovirus infection may be the cause in immunocompromised patients
  • Vasculitis
  • CKD
  Again the pathogenesis is not fully understood but is thought to relate to biliary stasis and/or gallbladder ischaemia. In a proportion of cases infection is the primary cause but it is thought infection is normally secondary to established inflammation.

Question 45

Signs of acute cholecystitis

Answer 45

• RUQ abdominal tenderness
  
  • Murphy’s sign positive:palpating the RUQ whilst the patient breathes in deeply causes pain
• Abdominal mass
  
  • Due to distended gallbladder (present in 30-40%)
• Pyrexia
• Tachycardia
• Hypotension (in severe cases)

Question 46

Symptoms of Acute cholecystits

Answer 46

• Nausea and vomiting
• Fever
• Right upper quadrant abdominal pain
  
  • Severe and lasting >30 minutes
  • Preceding history of biliary colic
• Referred right shoulder tip pain

Note: jaundice should not be present. If jaundiced, this may suggest Mirizzi syndrome, CBD stone or ascending cholangitis.

Question 47

Gold standard investigation for acute cholecystits

Answer 47

Abdominal ultrasound

Question 48

1st line investigations for acute cholecystitis

Answer 48

• FBC:leukocytosis with neutrophilia
• LFTs:usually normal in uncomplicated disease; derangement suggests Mirizzi syndrome, obstructing CBD stone, or cholangitis
• U&Es: may be deranged with an acute kidney injury secondary to infection
• Coagulation profile: assess the synthetic function of the liver and required prior to surgical intervention
• Venous blood gas: assess for degree of lactic acidosis
• Inflammatory markers: an elevated CRP would be expected
• Transabdominal ultrasound:first-lineimaging modality of choice
  
  • Positive Murphy’s sign on palpation with the probe
  • Thickened gallbladder wall (≥3mm)
  • Distended gallbladder with the presence of gallstones
  • Pericholecystic fluid

Question 49

Other investigations for Acute cholecystitis

Answer 49

• CT abdomen:if ultrasound is inconclusive, CT may be conducted. Traditionally considered less sensitive than ultrasound, but this is debated. Has the advantage of being able to assess for other pathology.
• MRCP:NICE advise performing an MRCP when suspecting aCBDstone in cases where ultrasound hasnotdetected gallstones but shows adilatedCBD, and/orLFTsare abnormal.
  
  • ERCP may be performed for extraction of CBD stone, if found.
• Cholescintigraphy (HIDA) scan: not routinely performed, but consider if ultrasound is inconclusive. IV technetium-labelled HIDA is taken up by hepatocytes and excreted into bile. Cholecystitis is associated with cystic duct obstruction so the gallbladder willnotbe visualised.

Question 50

Differential diagnosis for acute cholecystitis

Answer 50

• Pancreatitis
• Peptic ulcer disease
• Cholangitis
• Appendicitis
• Basal pneumonia

Question 51

1st line management for Acute cholecystitis

Answer 51

Initial management should follow an ABC approach in those who are acutely unwell. The sepsis 6 protocol should be implemented when indicated.

• Nil by mouth
• IV fluidsand analgesia
• Intravenous antibiotics: requires broad-spectrum antibiotics with gram-negative and anaerobic cover, such as cefuroxime and metronidazole

Note: before cholecystectomy, CBD stones should be checked for: MRCP or on-table cholangiogram.

• Early laparoscopic cholecystectomy
  
  • Performwithin 1 week of diagnosis, but often performed within 72 hours (‘hot laparoscopic cholecystectomy’)
  • Delayed procedure (> 6 weeks from admission) if hot cholecystectomy not available or appropriate (‘interval laparoscopic cholecystectomy’)
  • Early cholecystectomy is associated with: lower complications, shorter hospital stay, improved quality of life and better patient satisfaction

Question 52

2nd line management for acute cholecystits

Answer 52

Urgent cholecystostomy

• Performed if early cholecystectomy is inappropriate due to suspected sepsis/gangrene/perforation
• Surgical insertion of a percutaneous cholecystostomy tube with a delayed elective cholecystectomy 2-3 months after admission

Question 53

Complications of acute cholecystitis

Answer 53

• Gallbladder empyema:acute inflammation results in the gallbladder filling with pus and can lead to perforation
• Gallstone ileus:when a gallstone passes from the biliary tract into the intestine via a fistula resulting in small bowel obstruction
• Acute cholangitis: infection of the biliary tree commonly caused by gallstones which move into the common bile duct
• Obstructive jaundice: if stone moves to CBD
• Procedure-related: bile duct injury

Question 54

Prognosis for acute cholecystitis

Answer 54

Prompt medical management with intravenous antibiotics and identification of sepsis alongside an early laparoscopic cholecystectomy is associated with a very good prognosis. In patients with biliary colic without cholecystitis, early laparoscopic cholecystectomy reduces the risk of future episodes and the risk of cholecystitis. Gallbladder perforation has a mortality of over 30%, whilst untreated acute acalculous cholecystitis has a mortality of up to 50%

Question 55

What is Murphys sign

Answer 55

Murphy’s sign is indicative of cholecystitis. As the patient breathes out, place your hand below the right costal margin. As the patient breathes in an inflamed gallbladder moves inferiorly, the patient catches their breath. To be considered positive, it should be absent on the left side.

Question 56

Define chronic cholecystitis

Answer 56

Chronic inflammation of the gallbladder +/- colic

Question 57

Pathophysiology of chronic cholecystitis

Answer 57

• Repeated lodging and dislodging of gallstone in CBD, causing inflammation and fibrosis of the gallbladder
• In some cases, there may not be lodging and dislodging of gallstones. Instead, gallstones within the gallbladder can cause irritation to the gallbladder and causes damage this way.
• Overtime, this leads to inflammtion, fibrosis and maybe even calcification. This is known as porcelain gallbladder. This makes the gallbladder visible on x-ray

Question 58

Clinical manifestations of chronic cholecystitis

Answer 58

• Flatulent dyspepsia
• Abdominal discomfort - RUQ pain (esp after meal)
• Distension
• Nausea
• Fat intolerance (fat stimulates cholecystokinin release and gallbladder contraction)

Question 59

Investigations of chronic cholecystitis

Answer 59

• Ultrasound - to image stone and assess CBD diameter
• MRCP - used to find CBD stones
• X-ray - may show porcelain gallbladder

Question 60

Differentials for chronic cholecystitis

Answer 60

• If symptoms persist post-treatment, consider:
  
  • Hiatus hernia
  • IBS
  • Peptic ulcer
  • Chronic pancreatitis
  • Tumour

Question 61

Management for chronic cholecystitis

Answer 61

• Cholecystectomy
  
  • ERCP + sphincterectomy prior to surgery

Question 62

Complications of chronic cholecystitis

Answer 62

Increased risk of gallbladder cancer

Question 63

Define Acute (ascending) cholangitis

Answer 63

Acute cholangitis refers to infection of the biliary tree characteristically resulting in pain, jaundice and fevers.

Question 64

Epidemiology of Acute cholangitis

Answer 64

• Acute cholangitis is relatively uncommon and presents as a complication of gallstones in about 1% of patients.
• Age > 50 years
• Affects men and women equally
• There appears to be greater incidence in caucasians, hispanics and Native Americans - following the distribution of gallstones.
• It occurs following ERCP in around 0.5 - 3%.
• Recurrent pyogenic cholangitis is seen in southeast Asian populations.

Question 65

Aetiology of acute cholangitis

Answer 65

• Choledocholithiasis, stones in the bile duct, is the most common cause of acute cholangitis. Acute cholangitis occurs due to impaired drainage and bacterial overgrowth.
• Benign stricture: leading to obstruction, may occur in the biliary tree for numerous reasons:
  
  • Chronic pancreatitis
  • Iatrogenic injury(during cholecystectomy)
  • Radio / chemo-therapy
  • Idiopathic
  e.g. primary sclerosing cholangitis is a chronic, progressive condition associated with ulcerative colitis. It is characterised by inflammation and stricturing of bile ducts.
• Malignant stricture: e.g. cholangiocarcinoma, pancreatic cancer and gallbladder cancer.
• Other:
  
  • Post-ERCP(normally related to inadequate drainage)
  • Blocked biliary stent
  • Extrinsic compression
  • Blood clots
  • Parasites(e.g.Ascaris lumbricoides) can cause blockage

Question 66

RF for Acute cholangitis

Answer 66

• Gallstones:the most common predisposing factor
• Stricture of the biliary tree:benign or malignant
• Post-procedure injuryof the bile ducts e.g. post-ERCP

Question 67

Pathophysiology of Acute cholangitis

Answer 67

Acutecholangitis almost always occurs due to bacterial infection secondary to biliary obstruction.

Biliary obstruction is often secondary to choledocholithiasis (gallstones in the biliary tree) or biliary strictures (both benign and malignant).

Obstruction causes cholestasis and promotes the growth of bacteria, most commonly gram-negative, which then cause an ascending infection. E. coli is the most common pathogen.

Question 68

Key presentations for acute cholangitis

Answer 68

Right upper quadrant (RUQ) abdominal pain, jaundice, and fever is known as Charcot’s triad and suggests a diagnosis of ascending cholangitis. It is seen in 20-50% of patients.

The addition of hypotension and change in mental state/ confusion (shock) is known as Reynolds’ pentad and is associated with biliary sepsis.

Question 69

Signs of acute cholangitis

Answer 69

• RUQ tenderness
• Scleral icterus
• Pyrexia
• Hypotension: part of Reynold’s pentad

Question 70

Symptoms of acute cholangitis

Answer 70

• RUQ abdominal pain
• Jaundice
• Fever: the most common feature
• Nausea and vomiting
• Malaise
• Pruritis
• Dark urine and pale stool (cholestasis)
• Confusion: part of Reynold’s pentad

Question 71

Investigations for acute cholangitis

Answer 71

• FBC:leukocytosis with neutrophilia
• LFTs:obstructive jaundice with raised ALP > ALT, and bilirubin
• U&Es: pre-renal acute kidney injury in sepsis
• CRP: acute-phase protein and marker of inflammation
• VBG: assess for acidosis and lactate if suspecting sepsis
• Blood cultures: ideally taken prior to commencing IV antibiotics
• Transabdominal ultrasound: first-line imaging modality to detect common bile duct dilatation and the presence of gallstones

Other:
- CT abdomen with IV contrast:if ultrasound is negative and there is a high suspicion of cholangitis
- MRCP:gold-standard for diagnosis and used for pre-intervention planning and has the highest sensitivity. However, not as readily available so CT tends to be performed first
- ERCP:endoscopic investigation and intervention. Usually preceded by imaging (e.g. ultrasound and CT); many gastroenterologists ask for an MRCP prior to ERCP.

Question 72

Differentials for acute cholangitis

Answer 72

• Acute cholecystitis
• Peptic ulcer disease
• Pancreatitis
• Hepatic abscess
• Appendicitis
• Biliary colic

Question 73

Medical management for acute cholangitis

Answer 73

Initial management should follow an ABC approach in those who are acutely unwell. The sepsis 6 protocol should be implemented when indicated

• Intravenous antibiotics: broad-spectrum antibiotics with gram-negative and anaerobic cover e.g. cefotaxime and metronidazole for 4-7 days
• IV fluids: patients are often septic and require rehydration
• Analgesia: if needed, and tailored to patients’ needs.

Question 74

Surgical and non-surgical management for acute cholangitis

Answer 74

• Biliary decompression:
  
  • ERCP: first-line procedure usually performed within 24-48 hours. Allows for endoscopic exploration of the biliary tract with the removal of gallstones to facilitate drainage. Sphincterotomy may be performed to reduce the risk of future blockage.
  • Percutaneous trans-hepatic cholangiography (PTC): if ERCP fails, PTC is an alternative measure which allows access to the biliary tract via the liver.
  • Surgical drainagemay be carried out in patients where minimally invasive techniques described above are not possible. This involves a choledochotomy (incision into the common bile duct) and T tube insertionORlaparoscopic cholecystectomy with bile duct exploration
• Elective cholecystectomy: following successful biliary decompression, NICE recommends patients have a laparoscopic cholecystectomy to reduce future gallstone-related complications
• Those with strictures need the cause identified (if not already) and may require further surgery/endoscopic management. Malignancies are managed via appropriate MDTs.

Question 75

Complications for acute cholangitis

Answer 75

• Biliary sepsis:the commonest complication and typically presents with Reynolds’ pentad
• Acute pancreatitis:CBD stones can obstruct the pancreatic duct
• Hepatic abscess
• Risks of ERCP: duodenal perforation, pancreatitis, biliary sepsis, intra-abdominal bleeding

Question 76

Prognosis for acute cholangitis

Answer 76

The majority of patients recover quickly with effective resuscitation, initiation of antibiotics and adequate biliary drainage. The prognosis is worse if decompression is delayed or emergency surgical drainage is required (rather than non-surgical). Factors that predict a poor prognosis include high fever, hyperbilirubinaemia, hypoalbuminaemia, and older age.

Question 77

Define Primary biliary cholangitis (PBC)

Answer 77

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune condition characterised by granulomatous destruction of the intrahepatic biliary ducts, leading to cholestasis and subsequent leakage of bile into the circulation.

Question 78

Epidemiology of PBC

Answer 78

• Rare disease with a prevalence of < 0.05%
• Middle-aged:peak incidence between 45 and 60 years old
• Female gender: ten times more common in females

Question 79

Aetiology of PBC

Answer 79

Cause is unknown but its thought to be immunological and serum anti-
mitochondrial antibodies (AMA) are found in almost all patients. This allows T-cells to target the cells in the intrahepatic ducts and destroy them.

• Environmental trigger and genetic predisposition seem to play a part in loss of immune tolerance to self-mitochondrial proteins.

Question 80

RF for PBC

Answer 80

• Female gender
• Autoimmune conditions
• Family history
• Past pregnancy
• Smoking
• Excessive use of nail polish and hair dye
• Chronic urinary tract infection

Question 81

Pathophysiology of PBC

Answer 81

The inflammatory process coupled with trapping of bile acids in the liver leads to progressive fibrosis, cirrhosis, and eventually liver failure.

The presence ofanti-mitochondrial antibodies (AMAs) has been observed in almost all patients with PBC, further reinforcing the likely autoimmune nature of the condition.

Up to 50% of PBC patients have at least oneassociated autoimmune condition, such as:

• Sjögren’s syndrome (25%)
• Raynaud’s phenomenon (25%)
• Autoimmune thyroid disease (25%)
• Rheumatoid arthritis (20%)
• Systemic sclerosis(10%)

Question 82

Key presentations of PBC

Answer 82

The classic presentation of PBC is with significant itching in a middle-aged female. Some patients may be asymptomatic and be simply diagnosed on a routine blood test demonstrating abnormal LFTs (e.g. raised ALP).

Question 83

Signs of PBC

Answer 83

• Skin hyperpigmentation: due to increased melanin
• Clubbing
• Mild hepatosplenomegaly
• Xanthelasma and xanthomata (late sign) - due to leakage of cholesterol
• Scleral icterus (late sign)

Question 84

Symptoms of PBC

Answer 84

• Pruritis (itchy skin) - leakage of bile salts
• Fatigue and weight loss
• Dry eyes and dry mouth - Sjögren’s syndrome
• Obstructive jaundice (late sign) - due to leakage of bile and conjugated bilirubin
  
  • Icteric
  • Pale stool and dark urine

Question 85

Primary investigations of PBC

Answer 85

• Antimitochondrial antibodies (AMA):present in 95% of patients (highly specific)
• Antinuclear antibodies (ANA):present in 50% of patients
• Smooth muscle antibodies: 30% of patients; most associated with autoimmune hepatitis
• Raised serum cholesterol
• LFTs:an obstructive picture is seen with a raised ALP, GGT and bilirubin. AST and ALT may be mildly raised
  
  • Bloods in later disease: High bilirubin, low albumin and higher prothrombin time
• Coagulation profile: assess the synthetic function of the liver. Deranged in advanced disease
• Serum immunoglobulin:elevated IgM
• Transabdominal ultrasound: excludes other extrahepatic causes of cholestasis e.g. gallstones

Question 86

Other investigations of PBC

Answer 86

• MRCP:if the above tests are inconclusive, an MRCP should be conducted to look for intrahepatic biliary duct stenosis
• Liver biopsy: was previously used to diagnose all patients but non-invasive tests have largely replaced it. Must be performed if there is diagnostic uncertainty - look for granulomas around bile duct +/- cirrhosis

Question 87

Differentials of PBC

Answer 87

• Primary sclerosing cholangitis - AMA would not found
• Obstructive bile duct lesion
• Drug induced cholestasis - can do liver biopsy

Question 88

1st and 2nd line management for PBC

Answer 88

• Ursodeoxycholic acid
  
  • First-line agent in all patients
  • A bile acid analogue which dampens the inflammatory response, acts as an anti-apoptotic agent, and improves cholestasis
  • May be combined with obeticholic acid in those who do not respond to monotherapy
• Fat-soluble vitamin supplementation: cholestasis impairs fat absorption; vitamins A, D, E and K must be supplemented
• Cholestyramine: bile acid sequestrant for symptomatic relief ofpruritus
• Codeine phosphate: for diarrhoea
• Biphosphonates: for osteoporosis
• 2nd lineLiver transplantation: indicated in end-stage disease with liver cirrhosis; considered if complications of cirrhosis have occurred, based on disease severity (e.g. MELD score ≥15 ), if bilirubin values rising progressively >50–85 µmol/L and in some patients with intractable pruritus. Recurrence can occur in the graft but is not usually significant

Question 89

Monitoring of PBC

Answer 89

Regular LFT; ultrasound +/- AFP if cirrhotic (with chronic liver diseases, such as hepatitis and cirrhosis, AFP may be chronically elevated).

Question 90

Complications of PBC

Answer 90

• Malabsorptionof fat-soluble vitamins A, D, E and K due to cholestasis; may result in coagulopathy due to decreased bilirubin in gut lumen
• Hypercholesterolaemia:cholestasis is associated with hypercholesterolaemia
• Liver cirrhosis:end-stage disease results in fibrosis and eventual cirrhosis, whilst portal hypertension may cause ascites and variceal bleeding
• Hepatocellular carcinoma: 20-fold increased risk
• Metabolic bone disease:osteoporosis and osteomalacia

Question 91

Prognosis of PBC

Answer 91

Portal hypertension, advanced histological stage, and failure to respond to ursodeoxycholic acid are poor prognostic factors. Median survival is approximately 9 years, however, in patients diagnosed at an asymptomatic stage, survival is twice as high compared to those diagnosed at a symptomatic stage.

Question 92

Define Primary sclerosing cholangitis (PSC)

Answer 92

Primary sclerosing cholangitis (PSC) is an immune-mediated chronic liver disease that is characterised by inflammation, fibrosis and destruction of intrahepatic and/or extrahepatic bile ducts.

Question 93

Epidemiology of PSC

Answer 93

• PSC has a prevalence of 6.3 per 100,000 of the population, making it less common than primary biliary cholangitis (35 per 100,000).
• It is more common in Northern Europe and North America.
• Male sex:two-fold more common in males than females
• Age 40-50 years:the mean age of diagnosis is 40 years; it can occur at any age, including children

Question 94

RF of PSC

Answer 94

• Male
• History of inflammatory bowel disease:usually ulcerative colitis(UC); 4% of patients with UChave PSC, 80% of patients with PSC have UC
• Family history
• Some association with HLA-A1, B8 and DR3

Question 95

Pathophysiology of PSC

Answer 95

It is believed that the condition arises due to a complex interplay betweenpredisposing genetic elements and (undetermined)environmental exposures. A leading hypothesis for an environmental trigger is thehost gut microbiome.

Irrespective of cause, the damage to bile ducts leads to:

• Cholestasis
• Bile and toxin build up in the liver
• Bile duct strictures

All of the above contribute toliver fibrosis, cirrhosisand progression toend-stage liver disease.

Question 96

Signs of PSC

Answer 96

PSC is often asymptomatic in the early stages and detected on routine blood tests.

• Signs
  
  • Jaundice
  • Signs of complications:
    
    • Ascending Cholangitis: Charcot’s triad
    • Chronic liver disease:rare at first presentation, e.g. ascites or encephalopathy

Question 97

Symptoms of PSC

Answer 97

• Pruritis
• Fatigue
• RUQ/ epigastric abdominal pain
• Symptoms of underlying bowel disease: bloody stools, tenesmus, diarrhoea, steatorrhoea

Question 98

Primary investigations for PSC

Answer 98

• LFTs - raised ALP and raised bilirubin, raised GGT, raised ALT and AST if liver damage present, decreased albumin.
• Viral hepatitis screen:screen for HBsAg and anti-HCV in all patients
• Antibodies screening:
  
  • pANCA Anti-neutrophil cytoplasmic antibodies: positive in 33-88% of PSC patients, however is not specific
  • Antimitochondrial antibodies: positive in patients with PBC,notPSC
  • ANA: as part of a liver screen, as often elevated in autoimmune hepatitis and specific subtypes raised in PBC
  • Anticardiolipin antibodies - may be elevated
• MRCP:preferred diagnostic imaging modality showing multiple biliary strictures giving a‘beaded’ appearance; has largely replaced ERCP
• Abdominal ultrasound:rarely useful in diagnosis but useful to exclude alternative causes (e.g. choledocholithiasis)

Question 99

Gold standard of PSC

Answer 99

ERCP - but has been replaced by MRCP as MRCP is less invasive.

Question 100

Other investigations to consider for PSC

Answer 100

• ERCP: mainly requested if biopsies are required or for therapeutic reasons, e.g. relief of biliary strictures
• Liver biopsy:reserved for when the diagnosis is unclear, if there is a suspected overlap variant (e.g. PSC with autoimmune hepatitis) or in small duct PSC; biopsy may show fibrous, obliterative cholangitis often described as ‘onion skin’

Question 101

All management for PSC

Answer 101

• 1st line
  
  • Observation and lifestyle optimisation:encourage a healthy lifestyle, such as alcohol cessation and exercise
  • Cholestyramine:a bile acid sequestrant that is the first-line treatment for relief of pruritus; rifampicin is considered second-line
  • Fat-soluble vitamin supplementation:cholestasis leads to impaired fat absorption; to ensure the absorption of fat-soluble vitamins (ADEK), supplementation is required
• Other
  
  • Ursodeoxycholic acid - may improve LFTs
  • Antibiotics - for bacterial cholangitis
  End-stage liver disease:
  • Liver transplantation:indicated when expected survival after transplantation exceeds that predicted without transplantation

Question 102

Monitoring for PSC

Answer 102

The UK-PSC recommends anannual gallbladder ultrasoundscan and colonoscopyto detect pre-cancerous gallbladder cancer polyps, due to the increased risk ofcholangiocarcinomain patients with PSC. Consider cholecystectomy for gallbaladder polyps.

Question 103

Complications of PSC

Answer 103

• Cholangitis:inflammation of the biliary tree secondary to infection is common in patients with PSC
• Biliary strictures: narrowing of the extra-hepatic biliary tree occurs in 40-50% of patients
• Choledocholithiasis: an increased risk of gallstones
• Metabolic bone disease: increased risk of developing osteopaenia and osteoporosisdue to disturbed vitamin D and calcium metabolism
• End-stage liver disease:cirrhosis, portal hypertension and liver failure are a common outcome
• Cholangiocarcinoma:cancer of the biliary tree is the commonest cause of death in patients with PSC, with a lifetime risk of 20%
• Hepatocellular carcinoma:liver cancer has a reported prevalence of 2-4%
• Colorectal carcinoma:an increased risk of colorectal cancer in patients with UC who also have PSC compared to those with UC only

Question 104

Prognosis of PSC

Answer 104

Theaverage survivalof patients newly diagnosed with PSC is9.3 to 18 years. Despite the rare nature of this disease, PSC is the5thleading indication for liver transplantationin the USA. For those who receive aliver transplantation, the 5-year survival rate is approximately85%.

Question 105

How can you differentiate betqween PBC and PSC

Answer 105

Epidemiology:
PBC - More common in middle aged women
PSC - More common in middle aged men (can affect any age)

Pathophysiology:
PBC - Progressive destruction of only intrahepatic small and medium sized bile ducts
PSC - Progressive chronic inflammation or intrahepatic and/or extrahepatic bile ducts

Associated conditions:
PBC - Sjogrens, Raynauds, Autoimmune thyroid
PSC - IBD (particularly UC)

Presentation:
PBC - Often asymptomatic, fatigue and pruritis, jaundice, hepatomegaly
PSC - Similar to PBC, symptoms of IBD, features of ascending cholangitis

Serum tests:
PBC: Increased ALP + GGT, +/- conjugated bilirubin, Anti-mitochondrial antibodies
PSC: Increased ALP + GGT, +/- conjugated bilirubin, pANCA

Diagnosis:
PBC: Cholestatic LFT’s + history + examination + abdo USS
PSC: Cholestatic LFT’s + history + examination + MRCP

Management:
PBC: Ursodeoxycholic acid, Colestyramine, Fat soluble vitamins, End stage: liver transplant
PSC: Observation and lifestyle change, Colestyramine, fat soluble vitamins, End stage liver transplant

Median survival:
PBC: 7.5 years if symptomatic and 16 years if asymptomatic
PSC: 7-14 years

Complications:
PBC: Osteoporosis, Fat-soluble vitamin deficiences, end stage liver disease and hepatocellular carcinoma, hypercholesterolaemia
PSC: Osteoporosis, Fat-soluble vitamin deficiences, end stage liver disease and hepatocellular carcinoma, Cholangiocarcinoma, Ascending cholangitis, choledocholithiasis, colorectal cancel: relationship with UC

Question 106

Define acute pancreatitis

Answer 106

Acute pancreatitis refers to an acute inflammatory process involving the pancreas.

The 2 main causes of acute pancreatitis are gallstones and alcohol

Question 107

Epidemiology of acute pancreatitis

Answer 107

• In the UK there are an estimated 30 per 100,000 cases each year and the incidence is increasing globally
• The overall mortality rate in the UK is reported as around 5%, rising to 25% for patients with severe disease.
• In the UK, around 50% of cases are caused by gallstones, 25% by alcohol, and 25% by other factors.
• Increases with advancing age
• Afro-Caribbean ethnicity: risk is 2-3 fold higher in black populations than white
• Sex: alcohol-related pancreatitis is more common in males, whilst gallstone-related pancreatitis is more common in females
• Gallstone pancreatitis is more common in white women >60 years of age, especially among patients with microlithiasis.

Question 108

Aetiology of acute pancreatitis

Answer 108

I GET SMASHED:
I - Iatrogenic
G - Gallstones
E - Ethanol abuse
T - Trauma
S - Scorpion and spider bites
M - Mumps virus
A - Autoimmune
S - Steroids
H - Hypercalcaemia, hyperlipidaemia
E - ERCP
D - Drugs (valproate, azathioprine, thiazide diuretics, tetracyclines, mesalazine, oestrogen, sitagliptin, vidagliptin)

Gallstones

Gallstones are the most common cause of acute pancreatitis, they areresponsible for around 40-50% of cases. Gallstones migrate from the gallbladder to the biliary tree where they may cause obstruction of the ampulla. It is thought thatbiliary refluxandraised pressuresare responsible for the resultant pancreatitis.

Intracellular Ca2+ increases and causes the early activation of trypsinogen. In this situation, trypsinogen is cleaved (by cathepsin B) to trypsin, and trypsin degradation (by chymotrypsin C) is impaired and overwhelmed leading to a buildup of trypsin and thus increased enzymatic digestion of the pancreas and inflammation leading to extensive acinar damage

Alcohol

Alcohol has toxic effects on the pancreas and is implicated in around 25-35% of cases. Though it is known to increase the production of digestive enzymes, the exact mechanism by which it causes pancreatitis remains unclear.

Other causes include pregnancy or neoplasia.

Question 109

RF for acute pancreatitis

Answer 109

• Diet:intake of high glycaemic foods is associated with non-gallstone-related pancreatitis
• Obesity
• T2DM
• Family history: 65-80% of patients with hereditary pancreatitis have a mutation in the PRSS1 gene, whilst mutated SPINK1 is also implicated in some cases
• Gallstones
• Alcohol
• ERCP (endoscopic retrograde cholangiopancreatography) - use of contrast during ERCP has been linked to pancreatic inflammation.

Question 110

Pathophysiology of acute pancreatitis

Answer 110

Pancreatitis is caused by the release of enzymes, which causes autodigestion of pancreatic tissue.

The pancreas has bothendocrine and exocrine function. Endocrine function is governed by the islets of Langerhans and the hormones produced include insulin and glucagon.

The pancreatic ductal cells are responsible for its exocrine function. They produce the‘pancreatic juice’ composed of bicarbonate and digestive enzymes. One of these enzymes, trypsin, is key to the development of pancreatitis.

Under normal circumstances the pancreas releases zymogens - inactive enzyme precursors (trypsinogen in the case of trypsin). In pancreatitis, normal zymogen transport fails and trypsinogen is converted to trypsin within the pancreas leading to a cascade of zymogen activation. This triggers the recruitment of inflammatory cells and the release of inflammatory mediators.

This inflammation causes changes in the vascular bed, which leads to increased permeability and resultant oedema. The condition may be worsened by the release of inflammatory mediators and enzymes into the systemic circulation. This can result in a systemic inflammatory response (SIRS), sepsis and adult respiratory distress syndrome (ARDS).

Enzymes include proteases (causing further destruction), amylases (which can be used for diagnosis of pancreatitis) and lipases (which may result in fatty necrosis, and may also be used as a diagnostic feature)

Furthermore, destruction of blood vessels by enzymes causes haemorrhage. Destruction of the adjacent islets of Langerhans can result in hyperglycaemia as beta cells will be destroyed resulting in less insulin.

Question 111

Key presentations of acute pancreatitis

Answer 111

Acute pancreatitisshould be suspected in any person with:

• Acute upper or generalised abdominal pain, particularly if they have a history or clinical features of gallstonesoralcohol misuse

Question 112

Signs of acute pancreatitis

Answer 112

• Abdominal tenderness and guarding
• Abdominal distension - common, mainly due to leakage of fluid into the retroperitoneum
• Tachycardic and/or hypotensive - pt may be in shock
• Jaundice
• Cullen’s sign - periumbilical bleeding, secondary to intraperitoneal haemorrhage
• Grey Turner’s syndrome - flank bleeding secondary to retroperitoneal haemorrhage
• Fox’s sign: bleeding over the inguinal ligament secondary to retroperitoneal haemorrhage

Question 113

Symptoms of acute pancreatitis

Answer 113

• Severe upper abdominal pain: epigastric, RUQ or LUQ pain which may radiate to the back
• Nausea, vomiting and anorexia: common features
• Steatorrhoea: excess fat in faeces in acute-on-chronic pancreatitis
• Poor urinary output: due to insensible fluid losses, third-spacing (movement of fluid from intravascular to interstitial spaces), and vomiting

Question 114

Diagnostic investigations for acute pancreatitis

Answer 114

• Diagnostic
  
  • Serum amylase: amylase rises faster than lipase but also levels fall faster within 24-48hrs; less specific than lipase; isnotof prognostic value. Serum amylase may be raised in other conditions such as renal failure, so is non-specific
  • Serum lipase: more specific for acute pancreatitis; levels rise slower than amylase but have a longer half-life. Amylase is tested more frequently in the UK

Question 115

What tests would you do to ascertain severity of acute pancreatitis

Answer 115

• FBC:white blood cell count is required for severity scoring
• U&Es:renal function is required for severity scoring
• LFTs:required for severity scoring; an ALT of >150 U/L has an 95% positive predictive value forgallstone-related pancreatitis
• Arterial blood gas:arterial pO2and lactate are required for severity scoring
• Serum glucose:glucose levels are required for severity scoring
• Serum LDH:required for severity scoring (if AST is not available- raised AST/LDH is a sign of cell damage/pancreatitis )
• Serum calcium:calcium levels are required for severity scoring and identifying significant hypocalcaemia
• CRP: C-reactive protein is a predictor of severe pancreatitis

Question 116

Other investigations for acute pancreatitis

Answer 116

• Chest X-ray:to assess for the development of ARDS, as well as pleural effusions
• Erect chest X-ray: to exclude perforation - which also raises serum amylase
• Abdominal X-ray:to exclude bowel obstruction, as the clinical picture can overlap
• Abdominal ultrasound:to identify gallstones as an underlying cause or evidence of duct dilatation
• MRCP: type of MRI scan most commonly indicated in suspected gallstone pancreatitis to help evaluate for CBD stones.
• CT abdomen:a contrast-enhanced CT isnotordered routinely for diagnosis
  
  • Features includelocal oedemaandswelling, whilstnon-enhancing areassuggestpancreatic necrosis
  • A CT scan to assess for complications or severity should only be performed after6-10 days of admission

Question 117

1st line management for acute pancreatitis

Answer 117

The mainstay of acute pancreatitis management is supportive:

• IV fluid resuscitation: aggressive fluid replacement is required to compensate for insensible fluid losses, third-spacing, and vomiting
• Catheterisation: monitoring urine output is required to ensure appropriate rehydration
• Oxygen supplementation: if SpO2<94%, supplementary oxygen is required
• Opiate analgesia: the dosage of analgesia is titrated according to pain severity
• Early nutritional support: ‘resting’ the pancreas isnotevidence-based
  
  • Commenceoral feedingin people with mild pancreatitis if there is no nausea, vomiting, or abdominal pain
  • Enteral feeding(e.g. nasogastric feeding) is otherwise preferable
  • Parenteral feeding(e.g. total parenteral nutrition; TPN) is reserved for a small subset of people in whom enteral nutrition is not possible
• Antibiotics: not routinely indicated in acute pancreatitis and they should not be used prophylactically. Antibiotics should be commenced in patients with suspected/confirmed infected pancreatic necrosis, cholangitis or other infective source.

Question 118

Specific management for acute pancreatitis

Answer 118

• ERCP:**for those with gallstone related pancreatitis and cholangitis, removal of gallstones is required to relieve the obstruction within 72 hours
• Cholecystectomy: performed during the same admission for gallstonerelated pancreatitis; may be delayed in protracted, severe cases
• Alcohol cessation and withdrawal management: in alcohol-related pancreatitis, preventative measures are offered to prevent further episodes

Question 119

Monitoring for acute pancreatitis

Answer 119

During management:

• Hourly pulse, BP, urine output.
• Daily FBC, U&E, Ca2+, glucose, amylase and ABG.

Long-term monitoring is not necessary. Patients usually resolve after their acute attack. If they modify their risk factors, another episode may not recur later in life.

Question 120

Local complications of acute pancreatitis

Answer 120

Local complications

• Peripancreatic fluid collection:occurs<4 weeksafter initial presentation
• Pancreatic pseudocyst: occurs>4 weeksafter initial presentation
• Pancreatic abscess: usually due to infection of pseudocysts byE. coli
• Haemorrhage: infected necrosis may involve vascular structures → bleeding (may result in Grey-Turner’s sign)
• Necrotising pancreatitis : a severe, life-threatening subtype of acute pancreatitis
• Chronic pancreatitis: due to recurrent episodes of acute pancreatitis
• Local vascular complications: pseudo-aneurysm and venous thrombosis
• Fistula: resulting from inflammation surrounding the pancreas

Question 121

Systemic complications of acute pancreatits

Answer 121

• Acute respiratory distress syndrome:spread of inflammation to the lungs **has a high mortality rate (approximately 20%)
• Pleural effusions: exudative pleural effusion. Build-up of fluids between layers of pleura
• Aspiration pneumonia: in the event of excessive emesis, it is possible for aspiration of the vomitus
• Hypovolaemic shock: due to insensible fluid losses, third-spacing, and vomiting
• Renal failure:often due to pre-renal acute kidney injury secondary to significant intravascular depletion
• Paralytic ileus: the collection of pancreatic fluid in the retroperitoneum can obstruct the proximal intestine, resulting in ileus
• Hypocalcaemia:excessive pancreatic enzyme release causes fat necrosis, which increasesfree fatty acid(FFA) levels. The FFAschelate calcium saltsin the pancreas, resulting in calcium deposition in theretroperitoneum(fat saponification) → reduced calcium levels
• Hyperglycaemia: the destruction of the islets of Langerhans causes disrupted insulin release → raised glucose levels

Question 122

Prognosis for Acute pancreatitis

Answer 122

25% of acute pancreatitis cases are severe and associated with complications. Severe cases often require critical care input, and are associated with prolonged hospital stay and an increased mortality rate (25%), compared to the overall mortality rate (5%).

Question 123

What is necrotising pancreatitis

Answer 123

A severe subtype of acute pancreatitis

• Necrosis presents within thefirst 24-48 hoursresulting in the death of portions of the pancreas
• It should be suspected in those who continue to haveabdominal pain, nausea and feverdespite supportive management of acute pancreatitis
• Thekey diagnostic factoris non-enhancing low attenuating pancreatic tissue onCT imaging, which signifies necrosis
• Some hospitals performfine-needle aspirationto determine if necrotic tissue is infected, but false negatives are possible
• Walled-off necrosis(WON) occurs after 4 weeks, at which point percutaneous drainage or open necrosectomy may be indicated;earlynecrosectomy has ahigh mortality rate
• Despite the above, the presence of sepsis and multi-organ dysfunction may warrantearly surgery
• It carries apoor prognosisand has a high risk of becoming infected

Question 124

Define chronic pancreatitis

Answer 124

Chronic pancreatitis refers to inflammation of the pancreas. Unlike acute pancreatitis, chronic pancreatitis is irreversible. It is characterised by structural changes e.g. fibrosis, calcification and atrophy which leads to a decline in function of the pancreas.

Question 125

Epidemiology of Chronic pancreatitis

Answer 125

• Alcohol is the primary risk factor accounting for 80% of cases, whilst 20% of cases have an unknown cause
• The age at presentation varies with aetiology. Hereditary pancreatitis has a peak age at 10 to 14 years, juvenile idiopathic chronic pancreatitis at 19 to 23 years, alcoholic chronic pancreatitis at 36 to 44 years, and senile idiopathic chronic pancreatitis at 56 to 62 years.
• M>F
• Worldwide prevalence is around 4-5%

Question 126

Aetiology of chronic pancreatitis

Answer 126

• Recurrent bouts of acute pancreatitis
  
  • Ductal dilatation and damage to pancreatic tissue
  • Healing process involves laying down fibrotic tissue, causing stenosis and atrophy
• Alcohol
  
  • Increases digestive enzyme secretion while decreasing fluid and bicarbonate in the ducts. This can lead to blockage of duct as pancreatic juices become thick and viscous. This increases pressure in the duct and may cause distension. As well as this, it may cause early activation of digestive enzymes and therefore, autogestion.
  • Alcohol also stimulates release of cytokines, leading to an immune response which worsens the issue.
  • Calcium may also deposits on protein plugs
• Cystic fibrosis (main cause of chronic pancreatitis in children)
  
  • Mutations in ion transporter cause pancreatic secretions to become thick and sticky, leading to obstruction.
• Pancreatic tumours
• Trauma to pancreas
• Autoimmune pancreatitis - raised IgG4 (seen in many autoimmune disorders) trigger pancreatitis
• Congenital - Pancreas divisum - single pancreatic duct is not formed, but rather remains as two distinct dorsal and ventral ducts.

Question 127

RF for chronic pancreatitis

Answer 127

• Alcohol excess
• Smoking
• Family history
• Ductal obstruction e.g. gallstones, tumours, structural abnormalities
• Genetic - cystic fibrosis and haemochromatosis

Question 128

Pathophysiology of chronic pancreatitis

Answer 128

Chronic pancreatitis describes irreversible inflammation and/or fibrosis of the pancreas characterised by epigastric pain and progressive decline in endocrine and exocrine function. It often occurs secondary to repeated episodes of acute pancreatitis. Alcohol is responsible for up to 80% of cases. Other causes include ductal obstruction (e.g. gallstones), autoimmune pancreatitis, and cystic fibrosis.

The exact pathogenesis is poorly understood, but the initial insult is thought to occur in the pancreatic duct (e.g. gallstone), or to the acinar cells (e.g. alcohol). The outcome is an inflammatory reaction with autodigestion of pancreatic tissue due to inappropriate activation of trypsinogen to trypsin, with the end result of fibrosis and loss of function.

Question 129

Signs of chronic pancreatitis

Answer 129

• Epigastric tenderness
• Signs of liver disease due to alcohol excess e.g. jaundice and ascites
• Skin nodules (rare) - pancreatic lipase leaks into circulation and causes fat necrosis in soft tissue

Question 130

Symptoms of chronic pancreatitis

Answer 130

• Epigastric pain
  
  • Dull and radiating to the back
  • Improved by leaning forwards
  • Occurs 15 to 30 minutes after eating
• Steatorrhea and diarrhoea
  
  • Foul-smelling stools which are hard to flush. Stool contains fat as pancreatic function declines and food isn’t digested properly
• Nausea and vomiting
• Weight loss and fatigue
• Features ofdiabetes e.g. polyuria and polydipsia

Question 131

Primary investigations for chronic pancreatitis

Answer 131

• Transabdominal ultrasound: advised by NICE as thefirst-lineimaging modality. The pancreas may appear atrophic, calcified, or fibrotic
• CT abdomen:if ultrasound is suggestive, CT should be conducted and may demonstrate:
  
  • Pancreatic calcifications (80% sensitivity and 85% specificity)
  • Pancreatic atrophy
  • Duct dilatation

Question 132

Investigations to consider for chronic pancreatitis

Answer 132

• MRCP:usually performed if CT imaging is inconclusive; shows a ‘chain of lakes’ appearance due to alternating dilation and stenosis of pancreatic ducts
• Faecal elastase:used to assess exocrine functionandis**reduced in severe disease, but may be normal in mild disease; useful if imaging is inconclusive
• LFTs: abnormal if co-existent liver disease; AST>ALT suggests alcoholic liver disease
• HbA1c:islet cell destruction results in reduced endocrine function
• IgG4:associated with autoimmune chronic pancreatitis
• ERCP:again, may be performed if first-line investigations are inconclusive; has the added benefit as treatment of ductal pathology can also be conducted, e.g. gallstone removal

Question 133

Management for chronic pancreatitis

Answer 133

• Lifestyle modification:alcohol and smoking cessation
• Diet:low fat, high-calorie diet with fat-soluble vitamin supplementation (vitamin A, D, E, K)
• Analgesia: start with paracetamol and NSAIDs
• Pancreatic enzyme replacement: pancreatin (Creon) contains lipase, amylase and protease. Often given with a proton pump inhibitor as this increases the activity of the enzymes.
  
  • Pt may also require insulin replacement
• 2nd lineInterventional procedures:
  • Endoscopic stenting(fibrosis can lead to duct blockage and pain)
  • Coeliac plexus nerve blocks: may be considered in patients with intractable pain
  • Drainage of pseudocysts/ pancreaticojejunostomy
  • Pancreatectomy

Question 134

Monitoring for chronic pancreatits

Answer 134

Patients are recommended to be seen yearly for non-invasive testing, to include laboratory blood work and perhaps stool tests to monitor for specific complications, including:

• Cholestasis and biliary obstruction (LFTs)
• Malnutrition
• Baseline bone densitometry in high-risk patients
• Steatorrhoea (qualitative faecal fat)
• Diabetes (glucose).

Question 135

Complications of chronic pancreatitis

Answer 135

• Pancreatic complications
  
  • Malabsorption:reduced exocrine function leads to malabsorption
  • Duct obstruction:chronic inflammation and fibrosis leads to pancreatic duct obstruction which can contribute to pain
  • Pseudocysts:disruption of pancreatic duct architecture leads to pseudocysts; small cysts are observed, whilst larger ones may cause pain and rupture
  • Diabetes:islet cell destruction leads to reduced insulin production
  • Pancreatic cancer
• Local vascular complications: venous thrombosis and aneurysms
• Gastric varices: dilated submucosal veins in the lining of the stomach, which can be a life-threatening cause of bleeding
• Metabolic bone disease:increased risk of osteoporosis, likely due to malabsorption

Question 136

Prognosis for chronic pancreatitis

Answer 136

Almost all patients will develop exocrine insufficiency, and up to 75% will develop endocrine insufficiency. Survival is dependent upon the underlying cause, with a life expectancy of 55-72% in chronic pancreatitis due to alcohol excess.

Question 137

Define Alcoholic liver disease and its three stages

Answer 137

Alcoholic liver disease (ALD) has 3 stages of liver damage: fatty liver (steatosis), alcoholic hepatitis (inflammation and necrosis), and alcoholic liver cirrhosis. All are caused by chronic heavy alcohol ingestion.

Typically, alcohol consumption >100 g per day for 15-20 years increases the risk of alcoholic hepatitis. Approximately 8 g of pure ethanol is equal to 1 unit.

Question 138

Epidemiology of ALD

Answer 138

• The prevalence of alcohol-use disorders among men and women in the European region was 14.8% and 3.5%, respectively, in 2016. In the UK, it is estimated that 24% to 28% of adults drink in a hazardous or harmful way.
• M>F prevalence
• ArLD is the foremost health risk in developing countries and ranks third in developed countries.
• The mortality related to liver cirrhosis increases with age.
• Rising numbers of people are dying from liver disease associated with alcohol, particularly in young age groups. Mortality from ArLD is estimated at 9.0 per 100,000 people under 75 years old.

Question 139

RF for ALD

Answer 139

• Prolonged and heavy alcohol consumption
• Hepatitis C - increased risk of cirrhosis
• Female sex - ALD develops more rapidly and occurs at lower drinking levels in women than in men. However, most patients with ALD are male.
• Genetic predisposition - genes encoding enzymes that metabolise both alcohol and acetaldehyde, and pro-inflammatory (tumour necrosis factor [TNF]-alpha) and anti-inflammatory cytokines (interleukins 6 and 10), may influence the predisposition to ALD and cirrhosis.
• Increasing age >65
• Obesity

Question 140

Pathophysiology of ALD

Answer 140

Alcohol is metabolised mainly in the liver, through 2 main pathways: alcohol dehydrogenase and cytochrome P450 2E1.

Alcohol dehydrogenase is a hepatic enzyme that converts alcohol to acetaldehyde, which is subsequently metabolised to acetate by the mitochondrial enzyme acetaldehyde dehydrogenase. Alcohol dehydrogenase and acetaldehyde dehydrogenase reduce nicotinamide adenine dinucleotide (NAD) to NADH (reduced form of NAD). Excessive NADH in relation to NAD inhibits gluconeogenesis and increases fatty acid oxidation, which in turn promotes fatty infiltration in the liver.

The cytochrome P450 2E1 pathway generates free radicals through the oxidation of NADPH to NADP. Chronic alcohol use upregulates cytochrome P450 2E1 and produces more free radicals.

Chronic alcohol exposure also activates a third site of metabolism: hepatic macrophages, which produce tumour necrosis factor (TNF)-alpha and induce the production of reactive oxygen species in the mitochondria.

People with alcohol-use disorder are usually deficient in antioxidants, such as glutathione and vitamin E. Therefore, oxidative stress promotes hepatocyte necrosis and apoptosis in these patients. Free radicals can also induce lipid peroxidation, which can cause inflammation and fibrosis. The alcohol metabolite acetaldehyde, when bound to cellular protein, produces antigenic adducts and induces inflammation.

Alcohol also affects the barrier function of intestinal mucosa, producing endotoxaemia, which leads to hepatic inflammation.

As the immune system attacks the hepatocytes, patients develop alcoholic hepatitis. If alcohol consumption continues, this may progress to cirrhosis.

Question 141

Pathophysiology of alcoholic hepatitis

Answer 141

The acetaldehyde formed from metabolism of alcohol can react with molecules in the liver, forming acetaldehyde adducts. These are recognised as foreign and can be attacked by the immune system, causing further damage. At this point, the patient develops hepatitis.

This inflammatory response can also lead to the activation of stellate cells, which causes deposition of extracellular matrix proteins, generation of portal hypertension and fibrosis.

Question 142

Clinical manifestations of fatty liver

Answer 142

• Often, no symptoms or signs
• Vague abdominal symptoms of nausea, vomiting, diarrhoea are due to the more general effects of alcohol on the GI tract
• Hepatomegaly, sometimes huge, can occur together with other features of chronic liver disease

Question 143

Clinical manifestations of alcoholic hepatitis

Answer 143

• Patient may be well, with few symptoms, the hepatitis only being apparent on the liver biopsy in addition to fatty change.
• Mild to moderate symptoms of ill-health
  
  • Mild jaundice may occur
  • Signs of chronic liver disease (ascites, bruising, clubbing, Dupuytren’s contracture)
  • Anorexia
  • Asterixis
  • Diarrhoea and vomiting
  • High temperature, pulse and respiration
• In the severe cases
  
  • Abdominal pain is frequently present and a high fever is associated with
    the liver necrosis.
  • On examination there is deep jaundice, hepatomegaly and ascites with ankle oedema

Question 144

Signs and symptoms of Cirrhosis

Answer 144

• Patients can be very well with few symptoms
• On examination there are usually signs of chronic liver disease - ascites, bruising, clubbing and Dupuytren’s contracture
• There are features of alcohol dependency

Question 145

General signs of ALD

Answer 145

May not always be present:

• Hepatomegaly
• Abdominal pain
• Haematemesis
• Venous collaterals - engorged para-umbilical veins (caput medusae), present in advanced alcoholic liver disease.
• Splenomegaly
• Jaundice
• Palmar erythema
• Asterixis
• Ascites
• Weight loss
• Fatigue
• Confusion
• Pruritis
• Fever
• Nausea and vomiting
• Finger clubbing
• Dupuytren’s contracture
• Bruising - coagulopathy
• Withdrawal symptoms - high pulse, low BP, tremor, confusion, fits, hallucinations

Question 146

Investigations of ALD

Answer 146

A combination of clinical features and laboratory findings are used to make a diagnosis. A liver biopsy is usually reserved for severe case. It helps to assess severity, look for underlying cirrhosis and exclude alternative causes of liver disease.

• Screening tools e.g. CAGE - have they thought about cutting down on drink, have they felt annoyed at comments about their drinking, guilt about drinking, eye-opener in the morning?
• Baseline investigations:
  
  • Full blood count
  • Urea & electrolytes
  • Liver function tests
  • Bone profile
  • C-reactive protein
  • Magnesium
  • Coagulation(INR)
  • Non-invasive liver screen
  • Liver ultrasound
  • +/- septic screen(e.g. blood cultures, urines, ascitic cultures, chest x-ray)
• Findings - Elevated MCV, leukocytosis, raised AST and ALT (2:1 ratio), raised ALP and GGT, raised bilirubin, reduced platelets, raised prothrombin time.
• Ultrasound or CT - will show fatty infiltration
• Biopsy - may show mallary bodies, large mitochondria, neutrophil infiltrate, hepatocyte ballooning, fibrosis, cholestasis

Question 147

Severity scoring for ALD

Answer 147

• Maddrey discriminant function (DF) - used to assess the severity of alcoholic hepatitis. It is based on serum bilirubin and prothrombin time.
• Model for End-stage liver disease (MELD) - assesses severity
• Glasgow alcoholic hepatitis score (GAH) - predicts mortality among patients with alcoholic hepatitis. It is a slightly more complex score based on age, white blood cell count, urea, bilirubin and prothrombin time.

Question 148

General Management of ALD

Answer 148

• Alcohol cessation - alcoholics anonymous, disufiram can be used in chronic alcohol dependence (causes negative effects for patients due to acetaldehyde buildup - aversion therapy)
  
  • Manage alcohol withdrawal -
    
    • Diazepam
    • IV Thiamine to prevent Wernicke-Korsakoff encephalopathy (presents with
      ataxia, confusion and nystagmus) which occurs from alcohol withdrawal,
      occurs 6-24 hours after last drink and lasts up to a week
• Hydration
• Nutrition - diet high in vitamins and proteins

Question 149

Management for Alcoholic hepatitis

Answer 149

• Nutrition must be maintained with enteral feeding (high protein diet) and if necessary vitamin supplementation e.g. Vit K
• Steroids show short-term benefit e.g. prednisolone. Given to patients who score high on Maddrey Discriminant Factor scoring system.
• Screen for infections (ascitic fluid tap) and treat spontaneous bacterial peritonitis

Question 150

Alcoholic cirrhosis management

Answer 150

• Reduce salt intake
• Avoid aspirin and NSAIDs
• Liver transplantation

Question 151

Monitoring for ALD

Answer 151

Monitoring for alcoholic hepatitis - daily: LFTs, weight, U&Es, INR

Question 152

Complications of ALD

Answer 152

• Liver cirrhosis and related complications e.g. liver failure, hepatocellular carcinoma
• CNS - self neglect, low memory and cognition, cortical atrophy, retrobulbar neuropathy, fits, falls, neuropathy, hepatic encephalopathy
• Gut - obesity, diarrhoea and vomiting, gastric erosions, peptic ulcers, varices, pancreatitis, cancer, oesophageal rupture
• Blood - coagulopathy, thrombocytopenia, anaemia from: marrow depression, GI bleeding, alcoholism related folate deficiency, haemolysis, sideroblastic anaemia
• Heart - arrhythmias, high BP, cardiomyopathy, sudden death
• Reproduction - testicular atrophy, low testosterone and progesterone, high oestrogen, fetal alcohol syndrome

Question 153

Prognosis for ALD

Answer 153

• Fatty liver is reversible, but may progress to cirrhosis with continued drinking.
• 80% of people with alcoholic hepatitis progress to cirrhosis. Mild episodes of alcoholic hepatitis do not affect mortality but severe episodes associated with 50% mortality at 30 days. 1 yr after admission for alcoholic hepatitis, 40% mortality.
• 5 yr survival is 48% with cirrhosis, if drinking continues.

Question 154

Define non-alcoholic fatty liver disease

Answer 154

NAFLD refers to a fatty liver that cannot be attributed to alcohol or viral causes

Spectrum of disease - steatosis, steatohepatitis, fibrosis, cirrhosis (least to most severe)

Question 155

Epidemiology of NAFLD

Answer 155

• Commonest liver disorder in industrialised western countries
• Affects around 3/4’s of all obese individuals

Question 156

Aetiology of NAFLD

Answer 156

Results from fat deposition in the liver and usually affects individuals with metabolic syndrome:

• Obesity
• Hypertension
• Diabetes
• Hypertriglyceridemia
• Hyperlipidemia

Question 157

RF of NAFLD

Answer 157

• Older age
• Obesity
• Hypertension
• Diabetes
• Hypertriglyceridemia
• Hyperlipidemia

Question 158

Pathophysiology of NAFLD

Answer 158

Insulin resistance plays a role. Overtime, insulin receptors are less responsive to insulin so liver increases fat storage and decreases fatty acid oxidation. This means there is less secretion of fatty acids into the blood stream. There is also increased synthesis and uptake of free fatty acids from the blood (known as steatosis).

This causes fat droplets to form within hepatocytes and this may cause hepatocytes to swell up with fat and push nuclei to edge of cell.

Liver appears large, soft, yellow and greasy.

Overtime, the fat is vulnerable to degradation. Unsaturated fatty acids are especially vulnerable to things like ROS. This reacts to form a fatty acids radicals which can then react further with non-radicals such as oxygen and non-radical fatty acids. This carries on until one radical reacts with another radical to terminate the reaction.

This ultimately damages lipid membrane, leading to mitochondrial dysfunction and cell death. This generates inflammation. Inflammation + steatosis = steatohepatitis.

Damage also attracts neutrophils to the liver. Chronic steatoheptitis can trigger stellate cells to lay down fibrotic tissue (fibrosis).

The architecture then changes to the point where disease is now classed as cirrhosis

Question 159

Clinical manifestations of NAFLD

Answer 159

May be asymptomatic even at advanced stages

Sometimes symptoms are vague:

• Fatigue
• Malaise

Sufficient damage presents with:

• Hepatomegaly
• Pain in RUQ
• Jaundice
• Ascites
• Bruising
• Pruritisetc

Question 160

Investigations for NAFLD

Answer 160

Serum AST and ALT: Increase in ALT and sometimes AST. (Different to alcoholic liver disease where AST>ALT)

LFT: raised bilirubin, ALP, GGT, prothrombin time, low serum albumin

FBC: anemia and thrombocytopenia due to hypersplenism

Imaging: US, CT, MRI to look for fatty infiltrates

Biopsy: used to diagnose and assess severity

Question 161

Differentials for NAFLD

Answer 161

• Alcoholic liver disease
• Autoimmune hepatitis
• Hepatitis B and C
• Hemochromatosis
• DILI
• Primary biliary cholangitis
• Primary sclerosing cholangitis
• Wilson’s disease
• Alpha-1 antitrypsin deficiency

Question 162

Management for NAFLD

Answer 162

Steatosis and steatohepatitis is reversible if underlying cause is addressed. Cirrhosis is not reversible.

• Avoid alcohol consumption
• Reverse factors that contribute to insulin resistance
  
  • Healthy diet
  • Active lifestyle
  • Medication to control blood glucose
• Control risk factors e.g. bariatric surgery for obesity
• Address cardiovascular risk (commonest cause of death)
• Vitamin E may improve histology of fibrosis

Question 163

Monitoring for NAFLD

Answer 163

• Monitor for complications and progression (NASH, cirrhosis, DM)
• If cirrhotic, screen for hepatocellular carcinoma with ultrasound +/- alpha fetoprotein tumour marker test twice-yearly.

Question 164

Complications of NAFLD

Answer 164

• Ascites
• Varices and variceal haemorrhage
• Encephalopathy
• Hepatocellular carcinoma
• Hepatorenal syndrome - renal disease secondary to liver failure
• Hepatopulmonary syndrome - shortness of breath and hypoxemia caused by vasodilation in the lungs of patients with liver disease.

Question 165

Prognosis for NAFLD

Answer 165

The overall prognosis in patients with steatosis (fatty liver without evidence of active inflammation) is considered to be good and a majority of patients will remain stable throughout their lifetime. The same cannot be said of non-alcoholic steatohepatitis (NASH), which is considered the progressive form of NAFLD.

Patients who have NASH progress to cirrhosis 9% to 20% of the time. Up to one third of these patients will die from complications from liver failure or require liver transplantation.

Recurrent NAFLD following liver transplantation is now a well-recognised phenomenon. The incidence of the development of post-liver transplantation steatosis ranges anywhere from 25% to 100%, and the incidence of NASH ranges from a low of 10% to as high as 37.5%.

Hepatic steatosis affects up to 80% of patients with chronic hepatitis C infection. Concurrent fatty liver disease with hepatitis C includes increased disease progression, elevated risk of primary liver cancer, and a decreased response to antiviral therapy.

Question 166

Define Cirrhosis

Answer 166

Cirrhosis is a diffuse pathological process, characterised by fibrosis and conversion of normal liver architecture to structurally abnormal nodules known as regenerative nodules, surrounded by fibrotic tissue.

It can arise from a variety of causes (chronic alcohol use or viral attack) and is the final stage of any chronic liver disease. It can lead to portal hypertension, liver failure, and hepatocellular carcinoma. In general, it is considered to be irreversible in its advanced stages, although there can be significant recovery if the underlying cause is treated.

Question 167

Epidemiology of Cirrhosis

Answer 167

• Liver disease is the third biggest cause of premature mortality in the UK with 62,000 working life years lost.
• In Europe, cirrhosis related to either viral infection (21% with 13% of HCV infection and 7% of hepatitis B virus infection), or alcohol abuse (19%) are the main indications of liver transplant.

Question 168

Aetiology of Cirrhosis

Answer 168

• Common:
  
  • Chronic alcohol abuse (most common cause in the West)
  • Non-alcoholic fatty liver disease
  • Hepatitis B +/- D
  • Hepatitis C
• Others:
  
  • Hepatic vein events e.g. Budd-Chiari syndrome
  • Autoimmunity - primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis
  • Genetic disorders - hereditary haemochromatosis (iron overload), Wilson’s disease, Alpha1-Antitrypsin deficiency
  • Drugs e.g. amiodarone and methotrexate

Question 169

RF for Cirrhosis

Answer 169

• Alcohol misuse
• IV drug use
• Obesity

Question 170

Pathophysiology of Cirrhosis

Answer 170

• Chronic liver injury results in inflammation, matrix deposition, necrosis and angiogenesis all of which lead to FIBROSIS
• Liver injury causes necrosis and apoptosis, releasing cell contents and reactive oxygen species (ROS)
• This activates hepatic stellate cells and tissue macrophages (Kupffer cells)
• Stellate cells release cytokines that attract neutrophils and macrophages to the liver which results in further inflammation and thus necrosis and eventual fibrosis
• Kupffer cells phagocytose necrotic and apoptotic cells and secrete pro- inflammatory mediators:
  
  • Transforming growth factor-beta (TGF-beta) which leads to the transdifferentiation of stellate cells to myofibroblasts
  • Platelet derived growth factor (PDGF) which stimulates myofibroblast proliferation
• Increased myofibroblasts leads to progressive collagen matrix deposition resulting in fibrosis and scar accumulation in the liver
• This results in severe reduction in liver function as fibrosis is non- functioning
• This process is usually progressive and perturbs blood flow through the liver, thereby leading to increased pressure within the portal venous system, as well as shunting blood away from the liver.
• If the cause of fibrosis is eliminated e.g. treatment of viral hepatitis then resolution (complete reversal to near-normal architecture) of early fibrosis can occur
• In cirrhosis, regression (improvement, not reversal) occurs, which improves clinical outcomes
• The characteristic features of cirrhosis are regenerating nodules separated by fibrous septa and loss of lobular architecture within the nodules
• Two types:
  
  • Micronodular cirrhosis:
    
    • Regenerating nodules are usually < 3mm in size with uniform involvement of the liver
    • Often caused by alcohol or biliary tract disease
  • Macronodular cirrhosis:
    
    • These nodules are of varying size and normal acini (functioning unit of liver) may be seen within the larger nodules
    • Often caused by chronic viral hepatitis

Question 171

Clinical manifestations of Cirrhosis

Answer 171

• Leuconychia - white discolourations on nails due to hypoalbuminaemia
• Clubbing
• Palmar erythema
• Dupuytren’s contracture
• Spider naevi
• Xanthelasma - yellow fat deposits under skin usually around eyelids
• Gynaecomastia
• Loss of body hair
• Hepatomegaly
• Splenomegaly
• Bruising
• Ankle swelling and oedema
• Abdominal pain due to ascites

Question 172

Investigations for Cirrhosis

Answer 172

• Liver biopsy - GOLD STANDARD - confirms diagnosis and type and severity. Will see regenerative nodules and fibrotic tissue
• Bloods and LFTs - low albumin, raised prothrombin time, high AST, ALT, ALP, GGT, bilirubin, low platelets, low WCC, raised serum creatinine
  
  • Find cause e.g. alpha-fetoprotein may suggest hepatocellular carcinoma, hepatitis serology, auto-antibodies, alpha-1-antitrypsin
• Ultrasound and duplex-
  
  • Can show hepatomegaly (small liver in severe disease)
  • Splenomegaly
  • Hepatic vein thrombus
  • Ascites
  • Reverse flow in portal vein
• MRI
  
  • Increased claudate lobe size, smaller islands of regenerative nodules and presence of right posterior hepatic notch is more likely in alcoholic cirrhosis rather than viral cirrhosis.
  • Can detect tumours
• Ascitic tap
  
  • Sent for microscopy, culture and sensitivity (MC&S) - high neutrophils indicate spontaneous bacterial peritonitis.

Question 173

Differentials for Cirrhosis

Answer 173

• Constrictive pericarditis
• Budd-Chiari syndrome
• Portal vein thrombosis
• Splenic vein thrombosis
• Schistosomiasis
• Sarcoidosis
• Inferior vena cava obstruction

Question 174

Management for Cirrhosis

Answer 174

• Good nutrition is vital
• Alcohol abstinence
• Avoid NSAIDs, sedatives and opiates as these may precipitate gastro-intestinal bleeding or renal impairment
• Treatment of the underlying causes may arrest or reverse the cirrhosis - e.g. treatment for hepatitis, Wilson’s etc
• Those at risk should have Hep A & B vaccination
• Pruritus - Colestyramine
• Acites - fluid restriction and reduced salt intake, spironolactone
• Spontaneous bacterial peritonitis - antibiotics
• Encephaloathy - prophylactic lactulose and rifaximin for reduction in episodes
• If very advanced and no longer responsive to therapy then liver transplantation

Question 175

Monitoring for Cirrhosis

Answer 175

Patients should undergo 6 monthly ultrasound screening for early development of hepatocellular carcinoma

Question 176

Complications of Cirrhosis

Answer 176

• Coagulopathy; fall in clotting factors II,VII, IX & X
• Encephalopathy - asterixis (flapping tremor with wrist extended) & confusion/coma
• Hypoalbuminaemia resulting in oedema
• Hepatocellular carcinoma
• Spontaneous bacterial peritonitis
• Acute kidney injury, secondary to liver failure due to portosystemic shunt
• Portal hypertension:
  
  • Ascites
  • Oesophageal varices

Question 177

Prognosis for Cirrhosis

Answer 177

Overall 5 year survival is roughly 50%

Poor prognostic indicators = encephalopathy, low serum Na+, low serum albumin, high prothrombin time.

Question 178

Define portal hypertension

Answer 178

Normal portal vein pressures range from 5–10 mm Hg. The term portal hypertension refers to elevated pressures in the portal venous system. Venous pressure more than 5 mm Hg greater than the inferior vena cava pressure is defined as portal hypertension.

Portal vein is formed by the union of the superior mesenteric and splenic veins

Question 179

Aetiology of Portal hypertension

Answer 179

Pre-hepatic:

• Portal vein thrombosis
• Splenic vein thrombosis

Intra-hepatic:

• Cirrhosis (80% UK)
• Schistosomiasis (commonest worldwide)
• Sarcoidosis
• Myeloproliferative disease
• Congenital hepatic fibrosis

Post-hepatic:

• Right heart failure (rare)
• Budd-Chiari syndrome - obstruction of hepatic venous outflow
• Constrictive pericarditis
• Veno-occlusive disease

Question 180

RF for portal hypertension

Answer 180

• Cirrhosis
• Alcohol
• Congestive heart failure
• Hyper-coagulable state

Question 181

Pathophysiology of portal hypertension

Answer 181

• Following liver injury and fibrogenesis e.g. due to cirrhosis, the contraction of activated myofibroblasts and activation of stellate cells contributes to increased resistance to blood flow. There may also be increased resistance due to various mechanical causes as well as increased blood flow into the portal vein.
• This leads to portal hypertension → splanchnic vasodilation → drop in BP → increased cardiac output to compensate for BP → salt and water retention to increase blood volume and compensate → hyperdynamic circulation (high circulatory volume)/increased portal flow → formation of collaterals between the portal and systemic systems e.g. in the lower oesophagus and gastric cardia → gastro-oesophageal varices
• Venous collaterals/ varices can occur in many places:
  
  • Gastro-oesophageal junction - superficial varices that tend to rupture
  • Anterior abdominal wall
  • Rectum (30%)
  • Left renal vein
  • Diaphragm
  • Retroperitoneum

Question 182

Clinical manifestations of portal hypertension

Answer 182

Patients are often asymptomatic

Features of chronic liver disease

• Leukonychia (white discolouration on nails)
• Palmar erythema
• Spider telangiectasia
• Gynecomastia

Features of decompensated liver disease

• Encephalopathy
• Jaundice
• Ascites

Splenomegaly due to portal hypertension

Variceal bleeding

Question 183

Investigations for portal hypertension

Answer 183

• Abdominal ultrasound - dilated portal vein
• Doppler ultrasound - slow velocity and dilated portal vein
• Endoscopy - for presence of oesophageal varices

Question 184

Management for portal hypertension

Answer 184

• Treat underlying cause
• Salt reduction and diuretics
• Beta-blockers and nitrate to reduce blood pressure

Question 185

Complications for portal hypertension

Answer 185

• Varices and variceal haemorrhage
• Ascites
• Hepatopulmonary syndrome
• Liver failure
• Hepatic encephalopathy
• Cirrhotic cardiomyopathy

Question 186

Define Oesophageal varices

Answer 186

Oesophageal varices are abnormal, dilated veins that occur at the lower end of the oesophagus; they account for 10-20% of upper GI bleeds. They develop as a consequence of portal hypertension.

Question 187

Epidemiology of oesophageal varices

Answer 187

• Oesophageal varices are present in almost half of patients at the time of the diagnosis of cirrhosis
• Varices tend to develop in the lower oesophagus and gastric cardia
• The 1-year incidence of bleeding is 5% with small varices, and 15% with large varices.

Question 188

Aetiology of Oesophageal varices

Answer 188

• Secondary to portal hypertension:
  
  • Increased resistance: causes include pre hepatic (portal vein or splenic vein thrombus), hepatic (cirrhosis, schistosomiasis, sarcoid, myeloproliferative disease, congenital hepatic fibrosis) and post hepatic (e.g. right heart failure, constrictive pericarditis, Budd-Chiari syndrome - hepatic vein obstruction by tumour or thrombosis)
  • Increased flow
• Secondary to chronic liver disease/ cirrhosis

Question 189

RF for oesophageal varices

Answer 189

• Portal hypertension
• Cirrhosis
• Alcoholism
• Schistosomiasis infection

Risk factor for bleeding:

• Large varices:the single most important factor in determining bleeding risk
• Decompensated liver cirrhosis:a higher Child-Pugh class is associated with a greater bleeding risk

Question 190

Pathophysiology of Oesophageal varices

Answer 190

• Following liver injury and fibrogenesis e.g due to cirrhosis, the contraction of activated myofibroblasts contributes to increased resistance to blood flow.
• This leads to portal hypertension → splanchnic vasodilation → drop in BP → increased cardiac output to compensate for BP → salt and water retention to increase blood volume and compensate → hyperdynamic circulation (high circulatory volume)/increased portal flow → formation of collaterals between the portal and systemic systems e.g. in the lower oesophagus and gastric cardia → gastro-oesophageal varices

The lower one-third of the oesophagus drains into the portal vein via the left gastric vein. In portal hypertension, there is backpressure and these veins become engorged and dilated. There is also pooling of blood in these veins. If varices rupture, they can cause a life-threatening upper gastrointestinal (GI) bleed.

In contrast, the upper oesophagus drains directly into the azygos vein and then into the superior vena cava, so is not involved in the development of varices.

Question 191

Clinical manifestations of oesophageal varices

Answer 191

Patients can be asymptomatic if varices aren’t bleeding

• SignsFeatures of chronic liver disease
  • Leukonychia (white discolouration on nails)
  • Palmar erythema
  • Spider telangiectasia
  • Gynecomastia
  Features of decompensated liver disease
  • Encephalopathy
  • Jaundice
  • Ascites
  Splenomegaly due to portal hypertensionHypotensionTachycardiaPallor
• Symptoms
  • Haematemesis and malaena (dark sticky faeces)
  • Abdominal pain
  • Symptoms of blood loss (shock)
    
    • Light-headedness
    • Dyspnoea
    • Chest pain
    • Syncope

Question 192

Investigations for oesophageal varices

Answer 192

• Upper GI endoscopy: diagnostic and therapeutic
• FBC:anaemia
• LFTs and coagulation profile:assess the severity of liver disease and bleeding risk
• U&Es: urea is raised in an upper GI bleed (protein in RBCs is digested into urea in the GI tract)
• Venous blood gas: can be analysed within minutes and provides an estimate of the Hb. Also, a raised lactate suggests poor tissue perfusion and is associated with a significant bleed
• Crossmatch/group and save: ensures blood is ready to be transfused if needed
• Other investigations to consider
  
  • Erect CXR: if history and examination are unclear and a perforated ulcer is a possibility, an erect CXR should be performed for pneumoperitoneum (presence of air or gas in the abdominal (peritoneal) cavity); oesophageal rupture may demonstrate pneumomediastinum (abnormal presence of air or another gas in the mediastinum)

Question 193

Differential diagnosis for oesophageal varices

Answer 193

• Gastric varices
• Mallory-weiss tear
• Peptic ulcer disease
• Hiatal hernia

Question 194

Management for non bleeding oesophageal varices

Answer 194

It is recommended patients undergo endoscopic surveillance and are commenced on a beta-blocker

Question 195

Management for bleeding oesophageal varices

Answer 195

• Resuscitation
  
  • ABCDE approach: patients should ideally be resuscitated prior to endoscopy
  • IV fluids:useful if the patient is in shock, but important not to overhydrate as this can cause haemodilution
  • Blood products:blood transfusion; platelet transfusion if PLTs < 50 x10^9/L; fresh frozen plasma (FFP) if clotting is deranged or vitamin K
  • Terlipressin:ADH analogue and causes splanchnic vasoconstriction, reducing blood flow into the portal vein and thereby reducing portal pressure. Improves initial haemostasis and prevents rebleed. Octreotride is an alternative but is less effective
  • Prophylactic antibiotics:patients with variceal bleed and cirrhosis are at increased risk of bacterial infection. NICE recommend all patients should receive antibiotics; quinolones are usually used
  • Balloon tamponade:conducted in an emergency for uncontrolled bleeding as a temporary measure until definitive management can be performed
    
    • ASengstaken-Blakemore tubecan be inserted through the mouth/nose and lowered into the stomach where a balloon can be inflated to compress bleeding vessels

Question 196

Definitive management for oesophageal varices

Answer 196

• Oesophageal varices:endoscopic varicealband ligationis first line and is superior to sclerotherapy
• Gastric varices:endoscopicsclerotherapywith N-butyl-2-cyanoacrylate is first line. Sclerotherapyis a form of treatment where a doctor injects medicine into blood vessels or lymph vessels that causes them to shrink
• Transjugular intrahepatic portosystemic shunt(TIPS): for a variceal bleed (gastric or oesophageal) if endoscopic treatment fails

Question 197

Prophylaxis for oesophageal varices

Answer 197

• Beta-blocker:all patients should be commenced on a non-selective beta-blocker e.g. propranolol, as long termsecondary preventionto reduce portal pressure. This reduces rebleeding and mortality
• Endoscopic variceal band ligation(EVL): used asprimary preventionfor people with cirrhosis who have medium to large oesophageal varices. Performed at two-weekly intervals until all varices are eradicated, alongside a proton pump inhibitor to prevent EVL-induced ulceration

Question 198

Complications of oesophageal varices

Answer 198

• Rebleed: there is a risk of rebleed in the future; the risk is reduced with a beta-blocker
• Encephalopathy: patients who have a variceal bleed and liver disease often develop encephalopathy
• Infection: patients with variceal bleeds are at risk of infection, e.g. spontaneous bacterial peritonitis, and require prophylactic antibiotics

Question 199

Prognosis for oesophageal varices

Answer 199

Patients who have had a variceal bleed have a 1-year mortality of up to 40%. Prognosis can be improved by avoiding alcohol, losing weight (in fatty liver disease) and the use of prophylactic beta-blockers (e.g. propranolol). Prophylactic beta-blockers can reduce the risk of bleeding by 45-50%.

Question 200

Define Haematamesis

Answer 200

Haematemesis is simply defined as “vomiting blood”. It is caused by bleeding from part of the upper portion of the gastrointestinal tract. It may be bright red or look like coffee grounds.

(Upper GI tract bleeds may also present as malaena - dark sticky poo)

Question 201

Aetiology of Haematamesis

Answer 201

It has a wide range of possible causes, depending on the site of blood loss and the tissue that is actively bleeding.

Common causes:

• Peptic ulcers - ulceration can result in erosion into the blood vessels and can result in significant haemorrhage.
• Mallory-Weiss tear - typified by episodes of severe or recurrent vomiting, then followed by minor haematemesis. Such forceful vomiting causes a tear in the epithelial lining of the oesophagus, resulting in a small bleed.
• Oesophageal varices - caused by portal hypertension
• Gastritis/ gastric erosions
• Drugs - NSAIDs, aspirin, steroids, thrombolytics, anticoagulants
• Oesophagitis - inflammation of the intraluminal epithelial layer of the oesophagus, most often due to either gastric acid reflux (GORD) or less commonly from infections (typically Candida Albicans), medication (such as bisphosphonates), radiotherapy, ingestions of toxic substances, or Crohn’s disease.
• Duodenitis
• Malignancy

Rare causes

• Bleeding disorders
• Portal hypertensive gastropathy - refers to changes in the mucosa of the stomach in patients with portal hypertension
• Aorto-enteric fistula - pathologic communications between the aorta (or aortoiliac tree) and the gastrointestinal tract
• Angiodysplasia - abnormality with the blood vessels in the gastrointestinal (GI) tract.
• Haemobilia - bleeding into the biliary tree.
• Dieulafoy lesion - large arteriole most commonly in the stomach wall (submucosal) that erodes and bleeds
• Meckel’s diverticulum - outpouching or bulge in the lower part of the small intestine (congenital defect)
• Peutz-Jegher’s syndrome - benign hamartomatous polyps in the gastrointestinal tract
• Osler-Weber-Rendu syndrome - leads to abnormal blood vessel formation

Question 202

Hitstory and exam for haematemesis

Answer 202

• History and examinationThe key facts to ascertain from a history of haematemesis are:
  • Timing, frequency, and the volume of bleeding
  • History of dyspepsia, dysphagia, or odynophagia
  • Past medical history: varices? liver disease? past GI bleeds?
  • Smoking, drug and alcohol status
  • Use of steroids, NSAIDs, anticoagulants, or bisphosphonates
  • Co-morbidities: cardiovascular? respiratory? renal? malignancy?
  • Signs of chronic liver disease?
  On examination, it is important to assess specifically for epigastric tenderness or peritonism (inflammation of peritoneum), as well as features suggestive of a potential underlying cause, such as evidence ofvarices or liver stigmata. PR check for malaena.

Question 203

Primary investigations for haematemesis

Answer 203

• FBCs - acute bleeds may not show anaemia
• LFTs - may be deranged and show liver damage as potential cause
• U&Es - high urea out of proportion to creatinine, indicative of massive blood meal.
• All patients with haematemesis should have a Group and Save; those with significant haematemesis (especially suspected variceal bleed) should have at least 4 units of blood cross-matched.
• Oesophagogastroduodenoscopy (OGD) - definitive investigation and should be performed within 12hrs in most cases of acute haematemesis or as soon as possible if the patient is unstable.
• Erect chest X-ray - may also be required if a perforated peptic ulcer is suspected as the underlying cause.
• CT abdomen - can be useful in assessing any active bleeding in an unstable patient

Use GBS (Glasgow-Blatchford bleeding score) scoring system to risk stratify patients

Question 204

Management for haematemesis

Answer 204

Acute management

Patients with haematemesis can beextremely unstable.

• Rapid ABCDE assessment
• High flow O2
• Insert 2 large bore IV cannulae and take blood for FBC, LFT, U&E, clotting and crossmatch.
• Startfluid resuscitationif needed
• Insert urinary catheter to monitor and guide fluid replacement. Consider CVP line for monitoring fluid replacement
• Transfuse if significant Hb drop
• Correct clotting abnormalities - Vit K, fresh frozen plasma, platelets

Most cases will warrant anupper GI endoscopy.

If endoscopic control fails, surgery or emergency mesenteric angiography/embolisation may be needed

Suspected varices

• Terlipressin + IV antibiotics
• For uncontrolled variceal bleeding, a Sengstaken-Blakemore tube may be needed, before definitive management.

Peptic ulcer bleeds

• High risk: achieve endoscopic haemostasis. Start IV PPI. Treat if positive for H.Pylori.
• Low risk: endoscopic haemostasis not required. Consider early discharge and oral PPI. Treat if positive for H.Pylori.

Question 205

Define Hepatitis

Answer 205

Hepatitis is inflammation of the liver
Acute hepatitis is defined as hepatitis within 6 months of onset
Chronic hepatitis is defined as any hepatitis lasting for 6 months or longer

Question 206

Presentation of acute hep

Answer 206

• Can be symptomatic:
  
  • General malaise
  • Myalgia (muscle pain)
  • GI upset
  • Abdominal pain - particularly in right upper quadrant
  • With/without cholestatic jaundice (pale stools, dark urine)
  • Tender hepatomegaly
• Raised AST, ALP +/- bilirubin

Question 207

Causes of acute hep

Answer 207

• Infective:
  
  • Viral:
    
    • Hepatitis A and E
    • Herpes viruses e.g. EBV (Epstein Barr Virus), CMV (Cytomegalovirus), VZV (Varicella Zoster Virus)
  • Non-viral:
    
    • Leptospirosis
    • Toxoplasmosis
    • Coxiella (Q fever)
• Non-infective:
  
  • Alcohol
  • Drugs
  • Toxins/poisoning
  • Pregnancy
  • Autoimmune
  • Hereditary metabolic

Question 208

Presentation of chronic hep

Answer 208

Presentation:

• Can be asymptomatic e.g. hepatitis C infection
• +/- signs of chronic liver disease:
  
  • Clubbing
  • Palmar erythema
  • Dupuytren’s contracture (one or more fingers bending into palm of hand)
  • Spider naevi
• LFTs e.g. AST and ALT can be normal
• Compensated liver function can be maintained with cirrhosis
• If scarring is too severe then decompensated function:
  
  • Jaundice, ascites, low albumin, coagulopathy (clotting issues) and
    encephalopathy (confusion)

Question 209

Complications of chronic hep

Answer 209

• Hepatocellular carcinoma (HCC)
• Portal hypertension - varices and bleeding

Question 210

Causes of chronic hep

Answer 210

• Infection:
  
  • Hepatitis B (+/- D)
  • Hepatitis C
• Non-infective:
  
  • Alcohol
  • Drugs
  • Autoimmune
  • Hereditary metabolic

Question 211

Define Hep A

Answer 211

The Hepatitis A virus is a non-enveloped single-stranded RNA virus.

Question 212

Overview of Hep A

Answer 212

Spread via the faeco-oral route (contaminated food and water), hepatitis A belongs to theHepatovirusgenus of thePicornaviridaefamily.Hand washing and good hand hygiene are key to reducing transmission.

It causes aviral hepatitis, and is frequently seen in travellers to endemic areas and those engaging in higher-risk sexual activities.

Endemic in Africa and South America. It is uncommon in the UK.

The majority of adults infected experience symptoms (approx 70-95%). Commonly amild self-limiting illnessmanifesting with flu like symptoms, abdominal discomfort and nausea. Children under the age of 5 are frequently asymptomatic. Most infection is in childhood.

Hep A is only acute, not chronic.

Question 213

RF for Hep A

Answer 213

• Travel: those travelling to endemic areas
• Sexual:**high risk activities (e.g analingus, digital-rectal contact, chemsex), multiple partners
• Haematological disorders: factor VIII and factor IX concentrates have been implicated in transmission
• Occupational risks: for example laboratory or sewage workers
• IV drug users:**known to be at increased risk

Question 214

Pathophysiology and phases of Hep A

Answer 214

• Hep A is a picornavirus
• Replicates in the liver, is excreted in bile and then excreted in the faeces for about 2 weeks before the onset of clinical illness and for up to 7 days after
• Disease is maximally infectious JUST BEFORE the onset of jaundice
• Short incubation period of 2-6 weeks
• Causes ACUTE HEPATITIS ONLY
• 100% immunity after infection

Phases

Hepatitis A is said to follow four clinical phases (though significant variation exists).

1. Incubation:**Hepatitis A has a relatively long incubation period that may last from 2 - 6 weeks (mean 28-30 days).
2. Prodromal: Early part of the disease, characterised by fever, joint pain and rash. Flu-like symptoms may be present
3. Icteric:**In addition to jaundice, the icteric phase is characterised by anorexia, abdominal pain and change in bowel habit.
4. Convalescent:**Recovery phase as the body returns to normal and symptoms subside. Symptoms like malaise may last months.

Question 215

Key presentations of Hep A

Answer 215

Hepatitis A tends to cause a mild illness characterised by a flu-like illness and GI upset.

Question 216

Signs of Hep A

Answer 216

• Jaundice
• RUQ tenderness
• Hepatomegaly (85%)
• Splenomegaly (15%)
• Lymphadenopathy (5%)

Question 217

Symptoms of Hep A

Answer 217

• Abdominal discomfort
• Nausea
• Arthralgia
• Anorexia
• Diarrhoea
• Flu-like illness
• Pruritus
• Dark urine, pale stool
• Rash

Question 218

1st line investigations for Hep A

Answer 218

Serology

HAV-IgM is positive soon after symptoms develop and tends to remain detectable for a few months. This signifies active infection. HAV-IgG becomes positive 5-10 days after symptoms develop and remains lifelong. This signifies either recovery or evidence of vaccination.

• +ve HAV-IgM, +ve HAV-IgG:**Likely acute hepatitis A infection
• +ve HAV-IgM, -ve HAV-IgG:**May indicate acute infection or false positive IgM
• -ve HAV-IgM, +ve HAV-IgG:**Indicates previous infection or vaccine based immunity
• -ve HAV-IgM, -ve HAV-IgG:**No evidence of infection, may be very early or still in the incubation phase

Question 219

Other investigations for Hep A

Answer 219

Liver enzymes

• ALT/AST:**Tends to be significantly elevated, between 500 and 10,000 IU/L
• Bilirubin: Tends to be moderately elevated, between 50 and 200 micromols/L
• Prothrombin time:**Tends to be normal, may be elevated in complicated disease

Question 220

Management for Hep A

Answer 220

Management tends to be supportive except in the most severe cases.

The majority of patients do not need hospital admission. However any patient who is unwell or has significant liver impairment should be admitted and referred to hepatology.

Supportive management:

• General points: advise good oral hydration and rest. Alcohol should be avoided.
• Nausea: metoclopramide (max. 5 days) or cyclizine can be given if there is no significant liver impairment. In the presence of liver impairment discuss with specialists.
• Pruritus: chlorphenamine can be prescribed in the absence of liver impairment. In the presence of liver impairment discuss with specialists.
• Fulminant liver failure: rarely, interferon alfa given.
• Reduce transmission:**stay at home, good hygiene, avoid unnecessary contact and unprotected sex for 7 days after jaundice appears or symptoms began.

Notification and protection:

Clinicians should contact their local Health Protection Unit to allow contact tracing and monitoring of outbreaks. In England hepatitis A is a ‘notifiable disease’, meaning you must notify a Proper Officer of the local authority.

At risk contacts should be reviewed, if they have not been vaccinated, immunoglobulin should be considered. Typically the hepatitis vaccine will be offered.

Question 221

Monitoring for Hep A

Answer 221

Patients should be reviewed on a weekly basis for clinical review and repeat LFTs. Refer to specialist services if clinically worsening or persistently abnormal LFTs.

Question 222

Complications of Hep A

Answer 222

Rarely hepatitis A leads to more serious illness and complications needing specialist care:

• Relapsing hepatitis(may occur in 5-15%)
• Fulminant liver failure
• Prolonged cholestasis
• Others(interstitial nephritis, acute pancreatitis, red cell aplasia, Guillian-Barre syndrome)

Question 223

Prognosis for Hep A

Answer 223

Usually self-limiting. Fulminant hepatitis is rare. Chronicity doesn’t occur (only acute)

Question 224

Hep A Vaccine

Answer 224

Hepatitis A vaccine is recommended to those at risk of infection and at risk of complications of infection.

Individuals who should be offered vaccination include:

• Travel(to endemic areas)
• Chronic liver disease
• Sexual(MSM, high risk activities e.g analingus, digital-rectal contact, chemsex)
• Occupational risks
• IV drug users

Inactivated viral vaccine. It is available as a monovalent vaccine or in combination with hepatitis B or typhoid. The contents of each vaccine and the patients allergy status must be checked.

The first dose should be given at least 2-3 weeks prior to travel. Extra doses may be recommended if long term protection is needed.

Question 225

Define and Overview of Hep B

Answer 225

Hepatitis B is caused by the hepatitis B virus (HBV). It is an enveloped DNA virus that belongs to the Hepadnaviridae family and can cause acute or chronic hepatitis:

• Acute: can occur at any age. Majority of patients have a subclinical or anicteric (no evidence of jaundice) illness. In adults and older children, usually a self-limiting illness. In young children, more likely to develop chronic infection.
• Chronic: failure to clear the virus after acute infection. Defined as persistence of hepatitis B surface antigen (HBsAg) for >6 months. HBsAg is a viral protein that can be measured in the blood. Chronic hepatitis B (CHB) can lead to cirrhosis and hepatocellular carcinoma (HCC).

Incubation period of 1-6 months

Question 226

HBV Genotype

Answer 226

It is a DNA virus that contains a nucleocapsid and outer envelope. Its small DNA genome is contained within the nucleocapsid.

Genome

Based on the nucleotide sequence of the 3200 base pairs, HBV is classified into eight separate genotypes termed A-H. These genotypes are distributed differently throughout the world. The predominant genotype in the UK is A.

There are four major genes within the HBV genome.

• Surface (S) gene: encodes the small surface protein HBsAg
• Core (C) gene: encodes the hepatitis B core antigen (HBcAg), which also helps form the e antigen (HBeAg)
• Polymerase (P) gene: encodes DNA polymerase/reverse transcriptase
• X gene: encodes the hepatitis B x (HBx) protein

Protein products

• HBsAg: needed for construction of the outer HBV envelope
• HBcAg: composed within the nucleocapsid that contains the viral DNA.
• HBeAg: acts as an immune decoy to promote viral persistence. Presence is a marker of viral replication and infectivity.
• DNA polymerase: involved in the synthesis of DNA molecules. Has reverse transcriptase activity, which means it can form DNA from RNA.
• X protein: a transcriptional regulator that promotes cell cycle progression.

Question 227

Epidemiology of Hep B

Answer 227

• HBV can be transmitted perinatally, parenterally (e.g. infected needles), percutaneously or though sexual contact.
• The overall prevalence of HBV in the UK is estimated at 0.3%
• Worldwide, hepatitis B is a major health problem. An estimated 240 million people have chronic hepatitis B
• High prevalence countries are generally defined by a prevalence > 8%. These include Southeast Asia, China, Pacific islands and Sub-Saharan Africa.

Question 228

RF for Hep B

Answer 228

• IV drug users
• Healthcare workers
• Haemophiliacs
• Men who have sex with men
• Sexually promiscuous
• Haemodialysis

Question 229

Pathophysiology of Hep B

Answer 229

Once infected, HBV enters hepatocytes within the liver. Within hepatocytes the viral particle removes its outer envelope and forms covalently closed circular DNA (cccDNA). This DNA forms a template for transcription of the HBV proteins. cccDNA enters the nucleus of the cell where transcription takes place.

Once transcribed, core proteins, polymerase proteins and pregenomic RNA are packaged into core particles. Pregenomic RNA is then reverse transcribed into HBV DNA whilst surface proteins are attached to create the outer envelope. The full viral particle may then be secreted to infect other hepatocytes.

Question 230

Natural History of Hep B

Answer 230

HBV is not directly cytopathic. Liver injury is due to the interaction between virus and host immune response. HBV leads to an acute infection, which is most commonly subclinical. Persistent infection leads to chronic hepatitis B, which is characterised by five phases.

• Acute infectionThe majority (~70%) of patients have a subclinical or anicteric hepatitis. The remaining 30% present acutely with jaundice (icteric hepatitis). Fulminant hepatic failure is uncommon, occurring in 0.1-0.5 % of cases.Spontaneous clearance of hepatitis B is characterised by loss of HBsAg. This is usually accompanied by development of Hepatitis B surface antibodies (HBsAb or Anti-HBs), Hepatitis B core antibodies (HBcAb) and undetectable HBV DNA levels.
• Acute to chronicRisk of progression to chronic infection has an inverse relationship with age.
  • Perinatal transmission: 90% risk of chronic infection
  • Early childhood transmission: 25-50% risk of chronic infection
  • Adult transmission: < 5% risk of chronic infection
• Chronic infectionThese phases are not necessarily sequential.The five phases include:
  • Phase 1 - HBeAg +ve chronic infection(previously ‘immune tolerant’)
  • Phase 2 - HBeAg +ve chronic hepatitis(previously ‘immune reactive/clearance’)
  • Phase 3 - HBeAg -ve chronic infection(previously ‘inactive carrier’)
  • Phase 4 - HBeAg -ve chronic hepatitis(previously ‘reactivation phase’)
  • Phase 5 - HBsAg negative phase(previously ‘occult hepatitis B infection’) - recovery.

Question 231

Clinical manifestations of Acute Hep B

Answer 231

• Acute infection
  
  • Subclinical - no symptoms
  • Anicteric - non specific illness and no jaundice
    
    • Malaise, anorexia, nausea, fever, right upper quadrant pain, vomiting, arthralgia, urticarial rash
  • Icteric - presents same as anicteric, with jaundice
  • Fulminant hepatitis failure - rare, presents with jaundice, confusion and coagulopathy

Question 232

Clinical manifestations of Chronic Hep B

Answer 232

• Chronic infection
  
  • Asymptomatic carrier state
  • Chronic hepatitis - wide range of symptoms depending on the severity of hepatitis and underlying liver impairment. May mimic acute hepatitis B symptoms.
  • Cirrhosis - hepatomegaly, splenomegaly, portal hypertension
  • Decompensated cirrhosis - ascites, encephalopathy, jaundice, coagulopathy and GI bleeding.
  • Extra-hepatic manifestations - polyarteritis nodosa (PAN), glomerulonephritis, mixed cryoglobulinaemia, papular acrodermatitis

Question 233

1st line investigations for Hep B

Answer 233

Serology - antigens, antibodies and HBV DNA levels

HBV DNA- used as markers of infectivity and also reflects hepatitis B viraemia. HBV DNA levels fluctuate during chronic infection. They are used to determine the phase of chronic hepatitis B and form part of treatment indications.

HBsAg: HBV infection - acute or chronic
HBeAg: High levels of HBV replication & infectivity
Anti-HBe: Low levels of HBV replication and infectivity
Anti-HBc (IgM): Recent HBV infection
Anti-HBc (IgG): Recovered or chronic HBV infection
Anti-HBs: Immunity to HBV infection (natural or vaccination)
Anti-HBc (IgG) + Anti-HBs: Past HBV infection
Anti-HBc (IgG) + HBsAg: Chronic HBV infection

Question 234

Management of acute Hep b infection

Answer 234

• Acute infection
  
  • The majority of cases of acute hepatitis B are self-limiting so management is supportive.
  • Manage complications, if any - rarely, acute hepatitis B may cause a profound acute hepatitis or even fulminant hepatic failure.
  • Manage close contacts - HBIG and vaccine

Question 235

Management of chronic Hep b infection

Answer 235

• Avoid alcohol
• Antiviral therapy
  
  • Nucleos(t)ide analogues: act primarily by inhibition of reverse transcription of pregenomic HBV RNA into HBV DNA within hepatocytes. e.g. lamivudine, entecavir, and tenofovir among others. Entecavir and tenofovir have a high barrier to resistance. Good safety profile and well-tolerated. Given orally for long-term viral suppression. May be stopped in selected cases.
  • Pegylated Interferon: PegIFN has both antiviral and immunomodulatory activity. Exact mechanism is unclear. Thought to induce specific genes that interrupt with HBV replication cycle. Given weekly as subcutaneous injection for 48 weeks. Poor tolerability due to side-effects (flu-like illness, fatigue, weight loss, psychiatric disturbance, bone marrow suppression). Contraindicated in decompensated cirrhosis. High variability in response.
• Management of cirrhosis
• Liver transplantation if needed

Question 236

Monitoring of Hep B

Answer 236

Patients with cirrhosis need to be screened for HCC every 6 months. In those without cirrhosis, screening is less clear cut, but should be completed in high risk patients.

Question 237

Complications of Hep B

Answer 237

Cirrhosis

Fulminant liver failure

Decompensated liver disease

Hepatocellular carcinoma

Question 238

Prognosis for Hep B

Answer 238

Without treatment, the estimated 5-year incidence of cirrhosis in adults with chronic hepatitis B is up to 20%.

Globally, up to 1 million patients die from hepatitis B each year. Patients who are HBeAg-negative due to seroconversion (i.e. development of Anti-HBe) with low or undetectable HBV DNA levels have better outcomes due to the slower rate of disease progression and less development of cirrhosis and HCC. Five-year survival rates among people with untreated decompensated cirrhosis can be as low as 15%.

Question 239

HBV vaccine

Answer 239

• HBV VaccinationWithin the UK, hepatitis B vaccination now forms part of the universal vaccination programme for children. The vaccine is usually given as a combination vaccine (6 in 1) at 8, 12 and 16 weeks of age.The two most widely used HBV vaccines are recombinant vaccines.Indications for HBV vaccine
  • All newborns
  • All children and adolescents not vaccinated at both
  • High risk adults(e.g. healthcare workers, intravenous drug users, haemodialysis patients, etc)
  Hepatitis B immune globulinHepatitis B immune globulin (HBIG) is a substance that contains high levels of hepatitis B surface antibody. It can be given within hours of exposure to prevent infection. It should be given alongside the HBV vaccine.

Question 240

Define Hep C

Answer 240

Hepatitis C virus (HCV) is an infectious, hepatotropic virus belonging to the Flavivirus family. Infection may be acute and chronic.

Question 241

Epidemiology of Hep C

Answer 241

• UK prevalence >20,000
• Spread via blood transfusions, IV drug abuse, sexual contact. Vertical transmission is rare.

Question 242

RF for Hep C

Answer 242

• IV drug abuse
• Transfusions

Risk factors for progression:

• Male
• Older
• High viral load
• Use of alcohol
• HIV
• HBV

Question 243

Pathophysiology of Hep C

Answer 243

• RNA flavivirus
• 7 genotypes; genotype 1a and 1b account for 70% cases in USA and 50% in Europe
• Rapid mutations so envelope proteins change rapidly so its hard to develop a vaccine
• Early infection is usually mild and asymptomatic. 85% develop silent chronic infection. 25% get cirrhosis in 20 years and of these, 4% get hepatocellular carcinoma

Question 244

Clinical manifestations of Acute Hep C

Answer 244

• Most patients are asymptomatic
• 10% have mild influenza-like illness with jaundice and a rise in serum aminotransferases (ALT and AST)

Question 245

Clinical manifestations of chronic Hep C

Answer 245

Signs of cirrhosis, liver failure and hepatocellular carcinoma

Question 246

Investigations for Hep C

Answer 246

• Serology - HCV antibody, HCV RNA (indicates current active infection, decreasing levels indicate recovery)
• Other
  
  • Check for liver damage:
    
    • LFTs - raised AST and ALT
    • Liver biopsy
    • Non-invasive elastography

Question 247

Management for Hep C

Answer 247

• Stop alcohol consumption
• Acute HCV
  
  • If viral load is falling then no treatment may be required
  • Monitor patient to confirm viral clearance
• SC pegylated interferon-alfa 2A/B + oral Ribavirin no longer considered
  
  • Pegylated interferon increases risk of mental health side effects
  • Ribavirin causes haemolytic anaemia and anxiety
  • Ribavirin may still be used for some harder to treat genotypes
• Due to side effects and compliance issues, antiviral treatment that is interferon free is first line:
  
  • Triple therapy with direct acting antivirals (DAAs) - treatment is usually a once daily, oral tablet regimen for either 8 or 12 weeks
    
    • NS5A (initiates viral replication) inhibitor end in ASVIR e.g. ledipasvir, ombitasvir, ritonasvir
    • NS5B (needed for viral replication) inhibitors end in BUVIR e.g. sofosbuvir, dasabuvir

Question 248

Complications of Hep C

Answer 248

• Glomerulonephritis
• Cryoglobulinaemia - abnormal proteins in blood
• Thyroiditis
• Autoimmune hepatitis
• Polyarteritis nodosa (PAN) - systemic necrotising inflammation of blood vessels
• Polymyositis - inflammatory disease that causes muscle weakness affecting both sides of the body
• Porphyria cutanea tarda - porphyrin build up in skin

Question 249

Hep C prevention

Answer 249

• Hepatitis C prevention
  
  • No vaccination for Hep C
  • Previous infection does not confer immunity
  • Must screen blood products prior to transfusions
  • Precaution when handling bodily fluids

Question 250

Define Hep D

Answer 250

Hepatitis D is caused by the defective hepatitis D RNA virus (delta virus) that needs hepatitis B for replication.

Hepatitis D virus (HDV) is a unique RNA virus that can only establish infection in the human liver with the help of Hepatitis Bvirus (HBV). HDV has an outer envelope that contains the HBV surface antigen (HBsAg). Therefore, it can only establish infection in HBsAg-positive patients.

There are two key terms to recognise with HDV infection:

• Coinfection: acute hepatitis D infection acquired at the same time of hepatitis B infection. Typically indistinguishable from acute hepatitis B alone.
• Superinfection: development of acute hepatitis D infection in a patient with pre-existing hepatitis B infection. Usually more severe illness and higher risk of chronic infection (>90% of cases).

Question 251

Epidemiology of Hep D

Answer 251

• HDV spread through sexual contact, close household contact (e.g. abrasions, cuts, sharing toothbrushes), perinatally (although vertical transmission rare) or parenterally (e.g. contaminated needles).
• Hepatitis D has a worldwide distribution with 15-20 million carriers of HBsAg infected with HDV.
• Individuals with hepatitis D are always dually infected with hepatitis B.
• Endemic regions include Mediterranean areas, Middle East, Central and Northern Asia, East Africa, the Amazon Basin and Pacific islands.
• The UK has a low prevalence of hepatitis D (0-5%) and it is usually confined to high risk groups (e.g. intravenous drug users, historical recipients of multiple blood transfusions).

Question 252

RF for Hep D

Answer 252

IV drug users

Question 253

Pathophysiology of Hep D

Answer 253

Like other hepatotropic viruses, HDV is not directly cytopathic and liver injury occurs due to host immune-mediated injury.

Hepatitis D may lead to either acute or chronic infection

• Acute infection
  
  • Coinfection: variable clinical presentation ranging from mild to fulminant hepatitis. Usually a self-limited infection as HDV will not outlive the transient HBsAg positive status. Usually indistinguishable from acute hepatitis B. As with acute hepatitis B in adults, it usually results in complete recovery and rarely causes chronic infection (<2%).
  • Superinfection: more commonly there is an overt, severe hepatitis that is occasionally fulminant (i.e. acute liver failure). May present as an exacerbation of chronic hepatitis B, or new presentation of hepatitis in a previously unknown HBsAg carrier. Likely to become chronic hepatitis D in >90% of cases.
• Chronic infectionThe natural history of chronic hepatitis D is highly variable from asymptomatic to presentation with features of decompensated cirrhosis. The majority of liver damage that occurs in patients with hepatitis D and B coinfection is from HDV. This is because hepatitis D suppresses viral replication of HBV.Chronic hepatitis D is a severe disease with persistently abnormal liver biochemistry (i.e. liver function tests) and increased risk of progression to cirrhosis. Up to 80% of chronically infected patients develop cirrhosis within 5-10 years. A high proportion will subsequently die from liver-related complications (e.g. hepatocellular carcinoma, decompensated cirrhosis).

Question 254

Clinical manifestations of Hep D

Answer 254

• Asymptomatic carrierPatients will be asymptomatic and usually have evidence of subclinical hepatitis (e.g. deranged liver function tests). Usually seen in patients with chronic hepatitis D.
• HepatitisIn coinfection, symptoms are indistinguishable from acute hepatitis B. Clinical hepatitis ranges in severity and may be anicteric (without jaundice). In Superinfection there is usually a more severe hepatitis with onset of jaundice.
  • Nausea
  • Vomiting
  • Anorexia
  • Malaise
  • Right upper quadrant pain
  • Fever
  • Jaundice
• CirrhosisPatients who progress to chronic hepatitis D may have features of underlying cirrhosis (e.g. hepatomegaly, splenomegaly, portal hypertension). Stigmata of chronic liver disease (e.g. spider naevi) may be present
• Decompensated cirrhosisDecompensated cirrhosis refers to an inability of the liver to carry out normal function. It is characterised by the development of ascites, encephalopathy, jaundice, coagulopathy and GI bleeding.

Question 255

Investigations for Hep D

Answer 255

Serology - hepatitis D and B serological markers and viral levels are important to distinguish between both acute and chronic infection, as well as coinfection and superinfection.

• Assessment of liver injury -
  
  • FBCs, U&Es, bone profile, CRP, coagulation tests and LFTs
  • Imaging - CT, US
  • Liver biopsy

Question 256

Management for Chronic Hep D

Answer 256

• Chronic hepatitis D
  
  • Interferon alfa - usually given for a course over one year
  • Liver transplant indicated in some patients. Can use hepatitis B immunoglobulin and antiviral therapy to prevent reinfection after liver transplant.

Question 257

Complications of Hep D

Answer 257

• Cirrhosis
• Decompensated cirrhosis
• Hepatocellular carcinoma

Question 258

Prognosis for Hep D

Answer 258

Adult patients who develop coinfection with hepatitis D and B have a good prognosis. This is because the infection is usually self-limiting and there is a low chance of chronicity. However, superinfection is associated with a significant increase in morbidity and mortality with a very high chance of chronicity and associated complications.

Question 259

Define Hep E

Answer 259

Hepatitis E is a small, non-enveloped RNA virus that can lead to acute and chronic hepatitis.

Now recognised as themost common cause of acute viral hepatitisin many countries.

HEV is spread via thefaeco-oral route.

The spectrum of HEV is wide and depends on the underlyinggenotype,patient co-morbidities(e.g. immunosuppressed or immunocompetent) andpregnancy status. It can cause:

• Asymptomatic infections
• Acute viral hepatitis
• Chronic viral hepatitis
• Extra-hepatic manifestations

Question 260

HEV genotypes

Answer 260

HEV belongs to the genusOrthohepeviruswithin the familyHepeviridae. There are four genotypes of mammalian HEV that are known to affect humans:

HEV1 and HEV2

These genotypes arewaterborne obligate human pathogens. They usually cause epidemics of hepatitis E in developing countries and are most commonly seen in travellers returning from endemic areas. HEV1 is mostly found in Asia, while HEV2 is more commonly seen in Africa and Mexico.

HEV3 and HEV4

These genotypes are responsible for sporadic cases in developed and developing countries. In the UK, autochthonous (locally-acquired) HEV3 is themost common cause of hepatitis Eand the genotype is widespread in Europe. HEV4 is largely restricted to Southeast Asia, but an increasing number of cases are being identified in Europe.

HEV3 and HEV4 are considered aporcine zoonotic infection, although they have been identified in other mammalian species including rats, wild boar and rabbits. The primary host is pigs, but it is apathogenic in these animals. Eating contaminated pig meat or water can transmit the virus.

Question 261

Epidemiology of Hep E

Answer 261

• There is an estimated two million locally acquired HEV infections in Europe every year.
• Across Europe, there are areas ofhyperendemic HEV(predominantly genotype 3). These include Southwest France, Netherlands, Scotland, western Germany, Czech Republic, Abruzzo, central Italy and western/central Poland.
• Genotypes 1 and 2 are more prevalent in developing countries.
• Commoner in men
• Commoner than HAV in UK
• Can be harmful in pregnancy, causing death.

Question 262

Pathophysiology of Hep E

Answer 262

HEV is transmitted via the faeco-oral route. HEV1 and HEV2 are generally transmitted throughcontaminated water, whereas HEV3 and HEV4 are consideredzoonotic infections, acquired from infected animals (usually contaminated meat or infected water from the run off of slurry).

Once acquired, the incubation period is 2-6 weeks. This describes theperiod between exposure to the virus and development of clinical symptoms. HEV viraemia reaches its peak during the early infectious period, which is associatedwith a transient rise in IgM (acute antibody response) followed by a more sustained IgG response. During this acute infection, viral RNA may be detected in the blood or stool. It disappears from the blood within 3 weeks. The narrow viraemic window means the absence of viral RNA does not exclude acute infection.

The vast majority have asubclinical infection. In fact, < 5% of patients with HEV3 will develop clinical hepatitis. Patients who do develop a clinically apparent acute infection usually have a self-limiting illness. However, the condition is associated with several extrahepatic manifestations. In patients with pre-existing liver disease, there is an increased risk of decompensated cirrhosis or acute on chronic liver failure (ACLF).

Patients who are immunosuppressed are at risk of chronic infection (presence of HEV for > 3 months) and accelerated liver disease.

Question 263

Clinical manifestations of Acute Hep E

Answer 263

The majority of patients with acute hepatitis E will have a subclinical (asymptomatic) illness.

• Acute hepatitis
  
  • Jaundice
  • Fatigue
  • Nausea & vomiting
  • Abdominal pain
  • Pruritus
  • Flu-like illness
  • Hepatomegaly

Question 264

Clinical manifestations of Chronic Hep E

Answer 264

• Commonly asymptomatic
• Fatigue
• Rarely jaundiced

Question 265

Investigations for Hep E

Answer 265

• Primary investigations
  
  • Serology - IgM shows active infection; IgG shows recovery
  • Presence of HEV RNA - detected using PCR. Due to viraemic window, this may be negative but a negative result doesn’t exclude HEV.
  • LFTs - elevated AST and ALT
• Other
  
  • HEV antigen assay - check for presence of HEV antigen
  • Non-invasive liver screen if LFT’s deranged

Question 266

Management for Hep E

Answer 266

• Supportive treatmentIn the majority of patients, acute hepatitis E willclear spontaneously. Advice consists of good oral hydration and rest. Alcohol should be avoided.
• Management of complications, if any: e.g. acute liver failure or chronic liver disease
• Other
  
  • Anti-viral therapyRibaviron is the anti-viral therapy of choiceand usually reserved for patients with chronic hepatitis E that has failed to clear spontaneously. Chronic hepatitis E most commonly occurs in immunosuppressed patients so the first management strategy is reduction in immunosuppression if possible. If this fails to clear the virus, ribaviron can be considered.
  • Liver transplantationChronic hepatitis E may lead to progressive fibrosis/cirrhosis. Liver transplantation is a potential option in these patients.

Question 267

Complications for Hep E

Answer 267

Hepatic complications

• Fulminant hepatitis in pregnancy(20% mortality)
• Decompensated cirrhosis or ACLF
• Acute liver failure
• Rapidly progressive fibrosis(chronic hepatitis E)

Extrahepatic complications

• Neurological: wide variety of neurological problems associated with hepatitis E (e.g. Guillain-Barré syndrome, brachial neuritis, mononeuritis multiplex, meningoencephalitis).
• Haematological: thrombocytopaenia, MGUS, cryoglobulinemia
• Renal: glomerulonephritis
• Other: pancreatitis, autoimmune thyroiditis, polyarthritis, among others.

Question 268

Define Autoimmune Hepatitis

Answer 268

Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver of unknown aetiology. It is characterised by the presence of circulating auto-antibodies with a high serum globulin concentration, inflammatory changes on liver histology, and a favourable response to immunosuppressive treatment.

Question 269

Epidemiology of AIH

Answer 269

• A rare condition, with a prevalence of 1 in 10,000 individuals in the UK
• Gender:affects females more often than males (4:1)
• Age:type 1 AIH mainly affects adults whereas type 2 AIH affects children

Question 270

RF for AIH

Answer 270

• Associated with other autoimmune conditions such as, Hashimoto’s thyroiditis and primary biliary cholangitis
• HLA-DR3 and HLA-DR4 association

Question 271

Pathophysiology of AIH

Answer 271

Autoimmune Hepatitis (AIH) is a rare,chronic autoimmune liver diseasewhich can progress to cirrhosis. The aetiology is unclear and seems to be due to an interplay betweenenvironmentalandgeneticfactors. Some HLA haplotypes (HLA-DR3 and -DR4) are associated with the disease as shown in the table below. Most cases present withno identifiable precipitantalthough viral infection (e.g. hepatitis A) or medication (e.g. nitrofurantoin) have been proposed as possible triggers in some cases.

Associated antibodies include antinuclear antibody(ANA), anti-smooth muscle antibody(ASMA), anti-soluble liver antigen/liver-pancreas antibody(anti-SLA/LP), anti-liver kidney microsome antibody(anti-LKM1)and anti-liver cytosol 1 antibody(anti-LC1). Upto 25% of cases may not have detectable antibodies. There are two different types of autoimmune hepatitis, as seen below. Both produce different antibodies.

Essentially, these antibodies attack self-antigens and cause hepatitis.

Question 272

Clinical manifestations of AIH

Answer 272

25% of cases are asymptomatic and patients may be asymptomatic even if their disease has progressed to cirrhosis. If symptoms are present, most cases present with non-specific symptoms.

• SignsEvidence of chronic liver disease:
  • Jaundice
  • Spider telangiectasia
  • Gynaecomastia
  • Splenomegaly
  Evidence of acute liver failure (less common):
  • Jaundice
  • Ascites
  • Variceal bleed
  • Encephalopathy
• SymptomsGeneralised symptoms:
  • Fatigue
  • Fever
  • Malaise
  • Urticarial rash
  • Arthralgia
  • Weight loss
  • Nausea
  • Amenorrhoea

Question 273

Investigations for AIH

Answer 273

• Primary investigations
  
  • LFTs:elevated ALT and AST with normal or mildly elevated ALP. Bilirubin may also be raised
  • FBCs: anaemia, low WCC, low platelets
  • Immunoglobulins:IgG is raised in 85% of patients
  • Liver biopsy:performed on all patients. Interface hepatitis (inflammation of hepatocytes at the junction of the portal tract and hepatic parenchyma), also known as piecemeal necrosis, is seen in up to 98% of patients.
  • Viralscreen:exclude a viral cause for the hepatitis (e.g. EBV, CMV, and hepatitis A, B, C, E)
  • Autoimmunescreen:ANA, anti-SMA, Anti-SLA/LP, anti-LKM1, Anti-LC1
  • HereditaryScreen:exclude metabolic causes e.g. hereditary hemochromatosis and Wilson’s disease
• Other investigations to consider
  
  • Liver ultrasound: exclude biliary disease and can identify features consistent with chronic liver disease and cirrhosis
  • MRCP: helps exclude primary sclerosing cholangitis, if ALP disproportionately high.

Question 274

Management for AIH

Answer 274

• 1st line
  
  • Immunosuppression:prednisoloneandazathioprine are given together as first-line therapy to induce remission. Upon biochemical and histological remission, patients may stop treatment or go onto long term azathioprine maintenance therapy.
    
    • Prednisolone (suppresses immune response) and azathioprine (inhibits DNA synthesis - targets the rapidly proliferating B and T cells)
    • Alternate regimes are possible which involve budesonide or mycophenolate, for example
  • Hepatitis A and B vaccines: recommended in all patients
• 2nd line
  
  • Transplantation: may be needed in refractory cases where biochemical or histological remission is not achieved

Question 275

Complications of AIH

Answer 275

• Cirrhosis:approximately 30% of patients already have cirrhosis at presentation
• Hepatocellular carcinoma:4-6% risk and some patients may be screened regularly with AFP and liver ultrasounds
• Iatrogenic:
  
  • Osteoporosis:steroids increase the risk of osteoporosis along with chronic liver disease. DEXA scans should be conducted 1-2 yearly whilst on steroids
  • Cushing’s syndrome:associated with long-term steroid use

Question 276

Prognosis of AIH

Answer 276

Relapses are common and within 12 months of stopping treatment, following biological and histological remission, 50-90% of patients experience a relapse. 10-20% of patients will require a transplant. Nevertheless, the overall prognosis is good with a 10-year survival in excess of 90%

Question 277

Define Infective Diarrhoea

Answer 277

Gastroenteritis is inflammation all the way from the stomach to the intestines and presents with nausea, vomiting and diarrhoea.

Question 278

Epidemiology of Gastroenteritis

Answer 278

• 2nd leading cause of death in children under 5 globally - after Pneumonia
• Highest prevalence in South Asia and Africa

Question 279

Aetiology of Gastroenteritis

Answer 279

• Viral causes (most common)
  
  • Rotavirus - leading cause of diarrhoea illness in young children, affects nearly all children by the age of 4
  • Norovirus - most common among adults. Associated with; cruise ships, hospitals, restaurants - close proximity of people
  • Adenovirus: a less common cause and presents with a more subacute diarrhoea
  • Astrovirus
• Bacterial causes
  
  • Campylobacter jejuni (most common, associated with poultry)
    
    • Most common bacterial cause of gastroenteritis worldwide.
    • Common cause of travellers diarrhoea.
    • Spread by raw or improperly cooked poultry, untreated water, unpasteurised milk
  • E.coli - more common in children
    
    • Spread through contact with infected faeces, unwashed salads or water.
    • Enterotoxigenic E.coli main cause of travellers diarrhoea
    • E. coli 0157 produces the Shiga toxin. This causes abdominal cramps, bloody diarrhoea and vomiting. The Shiga toxin destroys blood cells and leads to haemolytic uraemic syndrome
  • Salmonella - more common in children
    
    • Spread by eating raw eggs or poultry and food contaminated with infected faeces of small animals
  • Shigella spp. - more common in children
    
    • Spread by faeces contaminating drinking water, swimming pools and food.
    • Shigella can produce the Shiga toxin and cause haemolytic uraemic syndrome.
  • Bacillus cereus
    
    • Spread through inadequately cooked food, typically fried rice left out.
    • Produces a toxin called cereulide that causes abdominal cramping and vomiting
    • When it arrives in the intestines it produces different toxins that cause a watery diarrhoea.
  • Yersinia enterocolitica
    
    • Eating raw or undercooked pork can cause infection.
    • Also spread through contamination with the urine or faeces of other mammal such as rat and rabbits.
  • Vibrio cholerae
    
    • Spread via faecal-oral route
    • Produces rice water stools
  • Antibiotic related - in general, antibiotics beginning with C can give rise to antibiotic
    induced Clostridium difficile diarrhoea:e.g. clindamycin, ciprofloxacin (Quinolones), co-amoxiclav (Penicillins), cephalosporins
    • Clostridium difficile replaces normal gut flora (e.g. when normal gut flora die due to antibiotic use) and causes necrosis giving rise to pseudomembranous colitis. This results in diarrhoea
• Parasitic causes
  
  • Giardia lamblia - most common
    
    • Spread via faecal-oral route
  • Entamoeba histolytica
  • Cryptosporidium

Question 280

RF for Gastroenteritis/infective diarrhoea

Answer 280

• Foreign travel
• PPI or H2 antagonist use
• Crowded area
• Poor hygiene

Risk factors for pseudomembranous colitis:

• Elderly
• Antibiotics
• Long hospital admission
• Immunocompromised i.e. HIV
• Acid suppresion (e.g. with PPI or H2 antagonist)

Question 281

Clinical manifestations of Gastroenteritis/Infective Diarrhoea

Answer 281

• Bloody diarrhoea - associated with bacterial infection (salmonella, shigella, e.coli)
• Vomiting
• Abdominal cramping
• Some causes (especially viral) present with:
  
  • Fever, fatigue, headache, muscle pain

Question 282

Investigations for Gastroenteritis/Infective Diarrhoea

Answer 282

• Bloods -
  
  • Low MCV and/or Fe deficiency e.g. in coeliac disease or colon cancer
  • High MCV if alcohol abuse or decreased B12 absorption e.g. coeliac disease or Crohn’s
  • Raised white cell count if parasites
  • Raised CRP, WCC and low albumin if C.diff
  • Raised ESR and CRP indicate infection, Crohn’s, UC or cancer
  • U&E: hypokalaemia in severe diarrhoea and vomiting
• Stool MCS - establish the causative organism and antibiotic sensitivities
• Abdominal xray - for toxic megacolon in case of C.diff
• Sigmoidoscopy with biopsy

Question 283

Differentials for Infective diarrhoea/gastro

Answer 283

• Appendicitis
• Volvulus
• IBD
• UTI
• Diabetes mellitus
• Pancreatic insufficiency
• Short bowel syndrome
• Coeliac disease
• Laxative abuse

Question 284

Management for Gastro/infective enteritis

Answer 284

• Isolate patient
• Good hygiene
• Treat causes
• IV fluids if severely dehydrated
• Oral rehydration and avoid high-sugar drinks in children (increases diarrhoea)
• Antibiotics, where appropriate
• Anti-motility agents e.g Loperamide
• Anti-emetics - treat vomiting e.g. Metoclopramide
• C.diff management
  
  • Metronidazole
  • Oral vancomycin
  • Rifampicin/Rifaximin
  • Stop C antibiotic
  • Stool transplant - for recurrent disease
  • Urgent colectomy if toxic megacolon

Question 285

Define Haemochromatosis

Answer 285

Haemochromatosis is a multisystem disorder of dysregulated dietary iron absorption and increased iron release from macrophages.

Question 286

Epidemiology of Haemachromatosis

Answer 286

• Type 1 (HFE-related) hereditary haemochromatosis most commonly occurs in individuals of northern European descent (1 in 10 people carry a mutation).
• It affects 1 in 200 European people.
• Middle age: most commonly presents at 40-50 years old.
• Men present earlier than women, due to menstruation being a protective mechanism.

Question 287

Aetiology of Haemochromotosis

Answer 287

• HFE gene mutation on chromosome 6. Autosomal recessive gene.
• High intake of iron and chelating agents e.g. ascorbic acid
• Alcoholics may have iron overload
• Chronic transfusions

Question 288

RF for haemochromotosis

Answer 288

• Family history
• Alcoholism
• History of chronic transfusion: only relevant inacquiredhaemochromatosis, for example in patients with thalassaemia

Question 289

Pathophysiology of Haemochromotosis

Answer 289

Hereditary haemochromatosis describes anautosomal recessivedefect in iron absorption due to a mutation in theHFEgene on chromosome 6, resulting iniron overload.C282YandH63Dare the two main missense mutations associated with hereditary haemochromatosis. Acquired haemochromatosis, on the other hand, usually occurs due to frequent transfusions of red blood cells or excessive intake of iron.

The HFE gene protein interacts with the transferrin receptor 1, which is a mediator in intestinal iron absorption. Iron is taken up by the mucosal cells of the small intestine inappropriately, exceeding the binding capacity of transferrin.

Hepcidin, a protein synthesised in the liver, is central to the control of iron absorption; it is increased in iron deficiency states and decreased with iron overload. Hepatic expression of the hepcidin gene is decreased in HFE haemochromatosis thereby facilitating iron overload.

In physiological states, the absorption of iron from the duodenum is tightly controlled. In haemochromatosis, this process is disrupted and there isunregulated absorption of ironfrom the gut resulting in iron overload.

Iron deposition in multiple tissues and organs leads to disruption of function, most commonly affecting theliver,pancreas, andheart.

Question 290

Signs of Haemochromotosis

Answer 290

Patients are usually asymptomatic, especially in early stages.

• Signs
  
  • Skin hyperpigmentation (bronze skin)
  • Arthritic joints
  • Testicular atrophy
  • Features of chronic liver disease e.g. hepatomegaly
  • Features of congestive cardiac failure e.g. peripheral oedema due to dilated cardiomyopathy
  • Signs of osteoporosis

Question 291

Symptoms of Haemochromotosis

Answer 291

• Early symptoms: lethargy, arthralgia (often in hands) and erectile dysfunction
• Loss of libido: hypogonadism due to cirrhosis and pituitary dysfunction
• Polyuria and polydipsia due to T1DM

Question 292

Investigations for haemochromotosis in primary care

Answer 292

• Check serum ferritin: will be high in patients with haemochromatosis. But, may also be high in other conditions so is non-specific
• Check serum transferrin saturation: if this is also high, can confirm that high serum ferritin was due to haemochromatosis and not other causes.
• Refer to secondary care

Question 293

Investigations for haemochromotosis in secondary care

Answer 293

• First lineBlood tests:
  • Serum transferrin saturation: elevated; see table below
  • Serum ferritin: elevated; often normal in early disease
  • Serumiron: elevated
  • LFTs: liver function may be deranged secondary to iron deposition
  • HbA1c: elevated due to damage to pancreatic beta cells
  • Initial screening: requires FBC, transferrin saturation, serum ferritinandserum iron
• Other investigationsGenetic testing:
  • Test for C282Y and H63D mutations associated with HFE gene; for testingfamily membersor symptomatic north European patients with the abnormal iron studies above
  Liver biopsy:
  • This is the most specific test and will show evidence of iron accumulation using Prussian blue (Perls) staining, whilst also assessing for fibrosis and cirrhosis
  • No longer required for diagnosis
  CT abdomen:
  • Increased attenuation of liver
  MRI:
  • Gives detailed picture of iron deposition on liver and heart.
  ECG and echocardiogram:
  • Assess for evidence of cardiomyopathy and/or heart failure
  Joint X-rays:
  • Characteristically demonstratechondrocalcinosis (calcium deposits in joints)
  Family screening:
  • All first degree relatives are screened with iron studies and, if deranged, should proceed to genetic testing

Question 294

Management for haemochromotosis

Answer 294

Venesection:first-line management

• Involves draining a small amount of blood, usually around 500 ml
• Initially offer weekly venesection until serum ferritin levels are20–30 lg/landtransferrin saturations <50%
• Following this, offermaintenance phlebotomy, depending on the rate of iron re-accumulation
• Aims of maintenance phlebotomy:normal FBC, serum ferritin <50 lg/l and transferrin saturations < 50%

Lifestyle:

• Patients should be advised to avoid alcohol and have a low iron diet

Iron chelation:

• Desferrioxamine can be used for patients with a contraindication to phlebotomy, such as severe anaemia

Question 295

Monitoring of haemochromotosis

Answer 295

• Monitor serum ferritin
• Monitor and treat complications

Question 296

Complications of Haemochromotosis

Answer 296

• Liver
  
  • Cirrhosis
  • Hepatocellular carcinoma: requires regular screening
• Endocrine
  
  • DM: due to damage to pancreatic beta cells
  • Hypogonadism: secondary to liver cirrhosis (increased oestrogens) and pituitary dysfunction. Can result in loss of libido and erectile dysfunction
• Cardiac
  
  • Dilated cardiomyopathy
  • Congestive cardiac failure
• Musculoskeletal
  
  • Pseudogout
  • Osteoporosis
• Dermatological
  
  • Skin hyperpigmentation

Question 297

Prognosis for Haemochromotosis

Answer 297

The prognosis associated with hereditary haemochromatosis depends on the degree of iron overload. The mean survival is approximately 20 years from diagnosis, whilst early diagnosis and intervention can significantly improve outcomes.

Liver cirrhosis and subsequent hepatocellular carcinoma is the most common cause of death. Therefore, patients require regular liver function tests and, if deranged, serum AFP and a liver ultrasound should be arranged.

Question 298

Define Wilsons disease

Answer 298

Wilson’s disease is an autosomal-recessive disease of copper accumulation and copper toxicity caused by mutations in the ATP7B gene, which is part of the biliary excretion of copper pathway.

Question 299

Epidemiology of Wilsons

Answer 299

• Wilson’s disease has a worldwide incidence of 30 cases per million.
• Adolescence: the mean age of onset is 17 years old, and the mean age of diagnosis is 20 years old.

Question 300

RF for Wilsons

Answer 300

• Family history: suggests inherited mutations in the ATP7B gene

Question 301

Pathophysiology of Wilsons

Answer 301

Wilson’s disease is a rare,autosomal recessivedisorder ofcopper accumulationand toxicity. It occurs due to mutations in theATP7Bgene on chromosome 13, resulting indysfunction in ATP-mediated hepatocyte copper transport.

The condition is characterised byincreased copper absorption from the small intestineanddecreased hepatic copper excretion.

Dysfunction in ATP-mediated hepatocyte copper transport causes a lack of copper transport into the bile and a lack of incorporation into ceruloplasmin, resulting in reduced biliary excretion of copper.

There is subsequent copper accumulation inhepatocytes, as well as leakage into serum causing raised free serum copper levels. The excess copper then accumulates in other tissues such as thebasal ganglia,kidney, andcornea, causing oxidative damage.

Question 302

Key presentations of Wilsons

Answer 302

3 main effects:

• Hepatic issues
• Neurological issues
• Psychiatric issues

Question 303

Signs and symptoms of Wilsons

Answer 303

• Neurological
  
  • Behavioural and psychiatric issues: such as depression and delusions, often the first presentation. Also, loss of libido and bad memory.
  • Parkinsonism: half of patients present with a tremor
  • Asterixis
  • Chorea
  • Dysarthria
  • Dystonia
  • Dementia
• Hepatic
  
  • Hepatosplenomegaly
  • Hepatitis and cirrhosis
  • Jaundice
  • Ascites
  • Asterixis and encephalopathy
• Renal
  
  • Renal tubular acidosis
  • Fanconi syndrome
• Opthalmological
  
  • Kayser-Fleischer rings: copper ring in iris.
• Haematological
  
  • Haemolytic anaemia
• Other
  
  • Blue nails
  • Arthritis
  • Grey skin
  • Hypermobile joints

Question 304

Primary investigations for Wilsons

Answer 304

• Primary investigations
  
  • Copper studies:
    
    • Reducedceruloplasmin andincreased24 hour urinary copper excretion is highly suggestive of Wilson’s disease.
      
      • Ceruloplasmin may be raised in cancer or inflammation, so other investigations are needed for diagnosis.
    • Increased freeserum copper butreduced totalserum copper. Remember, copper is normally bound to ceruloplasmin. Reduced ceruloplasmin means there is more free copper but a total reduction in the amount of copper in the blood
  • LFTs:deranged liver function due to copper accumulation resulting in hepatitis, which particularly causes an increase in AST and ALT
  • Genetic testing:ATP7B mutation; perform for all patients to confirm the diagnosis and facilitate family testing

Question 305

Gold standard test for Wilsons

Answer 305

Liver biopsy to test for copper content.

Question 306

Other investigations for Wilsons

Answer 306

• Liver biopsy:used to assess for hepatic copper accumulation, hepatitis and cirrhosis
  
  • Only required if the clinical signs and initial tests are inconclusive
• MRI brain:structural abnormalities within the basal ganglia
• Slit lamp exam: look for Kayser-Fleischer rings.
• Family screening:first degree relatives should be screened with LFTs, copper studies, and genetic analysis

Question 307

Management for Wilsons

Answer 307

• 1st lineCopper chelation: usually the first-line treatment. Chelators bind copper and facilitate renal excretion; D-penicillamine is most commonly used
  • Trientine hydrochloride: an alternative chelating agent
• Other
  • Lifestyle advice: high copper content foods such as shellfish should be avoided. However, dietary restriction cannot be used as sole therapy.
  • Liver transplantation:indicated in acute liver failure or decompensated cirrhosis

Question 308

Monitoring for Wilsons

Answer 308

Monitor FBC, urinary copper and protein excretion.

Question 309

Complications of Wilsons

Answer 309

• Liver failure:patients can present with acute liver failure or decompensation of pre-existing chronic liver disease. This may necessitate transplantation
• Renal stones: secondary to hypercalciuria
• Renal failure: often due to D-penicillamine therapy, rather than the disease itself
• Side effects of medication: nausea, rash, haematuria, nephrosis, lupus and reduced WCC, platelets and Hb.

Question 310

Prognosis for WIlsons

Answer 310

If detected and treated early, many patients can live a normal life with a normal life expectancy. Chelation therapy can reverse symptoms related to early liver and some neurological damage.

Question 311

Define Alpha-1 antitrypsin deficiency

Answer 311

Alpha-1 antitrypsin deficiency is a rare autosomal recessive disorder that causes liver and pulmonary disease.

A1AT is a type of serine protease inhibitor. Deficiency is called serinopathy.

Question 312

Epidemiology of A1AT deficiency

Answer 312

• A1AT deficiency is most common in people of European ancestry and is uncommon in people of Asian descent.
• Worldwide, there are > 3 million people affected by AATD.
• Equal sex prevalence.
• There is a bimodal distribution in clinical presentation. In neonates, AATD may cause hepatitis and in children it can cause decompensated cirrhosis. In adults, it is most commonly seen in the fifth decade of life with features of liver and/or lung disease.

Question 313

RF for A1AT deficiency

Answer 313

Family history: there may be a family history of early-onset COPD and/or AAT deficiency

Question 314

Pathophysiology of A1AT deficiency

Answer 314

Alpha-1 antitrypsin (A1AT) is aprotease inhibitormade in the liver which predominantly acts to protect the lungs from neutrophil elastase.

A1AT deficiency is a common inherited condition caused by a deficiency in A1AT, resulting inprotease-mediated damage, particularly in the lungs. The mutation is located on chromosome 14 and is inherited in anautosomal recessive/co-dominantfashion.

• GeneticsThe severity of the disease depends on the mutation of the protease inhibitor (Pi) allele.PiM is the normal allelewith 2 copies expressed, giving the genotype PiMM.A1AT deficiency is associated with various abnormal alleles, of which the most clinically relevant arePiSandPiZ. The table below is a simplified summary, however, to complicate matters heterozygous genotypes such as PiMZ also exist.
  • M: normal
  • S: slow
  • Z: very slow
• Liver effectsPatients with the PiZZ genotype are particularly at risk of liver cirrhosis. The mutation causes a change in the structure of the A1AT protein, resulting in aggregation and accumulation within hepatocytes as the protein is misfolded and gets stuck in the endoplasmic reticulum. This causes cell death leading to liver damage with jaundice, hepatitis, cirrhosis, and hepatocellular carcinoma.
• Lung effectsNormally, neutrophil elastase (also induced by smoking) destroy harmful causes of infection and inflammation, but can also destroys the elastin in the alveoli. A-1 antitrypsin usually regulates the elastase, but with an A1AT deficiency the elastase is able to destruct the elastin in the lungs.The disease primarily affects the lungs due to dysregulation of proteases leading to parenchymal destruction and subsequent panacinar emphysema, most severe in the lower lobes. This is in contrast to smoking which causes centriacinar emphysema, most prominent in the upper lobes. Acinus is the functional unit of the lung consisting of a bronchiole and its alveolus. Panacinar means that the entire unit is affected, whereas centriacinar means only the central part is affected.

Question 315

Clinical manifestations of A1AT defciency

Answer 315

• Key PresentationsEarly onset of COPD symptoms
• Symptoms
  • Respiratory
    
    • Dyspnoea and productive cough
    • Prolonged expiratory phase and wheeze with pursed-lip breathing
    • Weight loss
    • Barrel chested due to hyperexpanded lungs
  • Liver (liver symptoms only occur with certain genotypes that cause a misfolded protein that gets stuck in the endoplasmic reticulum of hepatocytes)
    
    • Jaundice
    • Hepatomegaly
    • Ascites
    • Inability to make coagulation factors
    • Buildup of toxins leading to hepatic encephalopathy
    • Portal hypertension and consequent complications

Question 316

Investigations for A1AT deficiency

Answer 316

• Serum A1AT levels:reduced with levels < 20 micromol/L
• Chest X-ray:hyperinflated lung fields
• Lung Function Tests:obstructive pattern with FEV1/FVC < 0.7
• LFTs:deranged and must be monitored due to the risk of hepatocellular carcinoma
• Liver biopsy: Stained with Periodic acid Schiff (PAS) which stains A1AT pink, and Diastase, which should destroy A1AT. If A1AT is mutant and stuck in ER, it will not respond to diastase = Periodic acid Shiff +ve and diastase resistant.
• CT chest:panacinar emphysema, most significantly in the lower lobes
• Genetic tests:allows identification of the mutated allele and the patient’s genotype, e.g. PiZZ

Question 317

Differentials for A1AT deficiency

Answer 317

• Asthma
• COPD
• Bronchiectasis
• Viral hepatitis
• Alcoholic liver disease

Question 318

Management for A1AT deficiency

Answer 318

• Respiratory
  
  • Smoking cessation:all patients should be advised regarding smoking cessation as this reduces the risk of respiratory disease
  • COPD treatment:if there is evidence of pulmonary disease, patients should be treated with short and long-acting bronchodilators, as well as inhaled corticosteroids, as per COPDguidelines.
  • A1AT augmentation:patients with markedly low A1AT levels with evidence of respiratory disease may be commenced on intravenous A1AT
  • Surgery: lung volume reduction surgery, or lung transplantation for end-stage, refractory lung disease
• Liver
  
  • Alcohol avoidance
  • Hepatitis A and B vaccinations
  • Liver transplantation: for end-stage, refractory liver disease

Question 319

Complications of A1AT deficiency

Answer 319

• Respiratory failure:much like COPD, these patients are at risk of respiratory failure, particularly type 2 respiratory failure
• Cirrhosis and hepatocellular carcinoma:patients should have their LFTs monitored and if there is any derangement, a serum AFP and CT abdomen should be performed to assess for malignancy
• Cholestasis: usually in children

Question 320

Prognosis for A1AT deficiency

Answer 320

The vast majority of deaths secondary to A1AT deficiency are due to respiratory failure rather than liver failure. The median age of death is 40 years old in smokers and 65 years old in non-smokers, thus highlighting the importance of smoking cessation.

Question 321

Define Liver cancer

Answer 321

Liver tumours may be primary or secondary. Most commonly, liver tumours are a result of metastases (90%)

Primary liver tumours are less common and may be benign or malignant, but most commonly are malignant.

Question 322

What are the two types of primary malignant and benign liver tumours

Answer 322

Malignant:
Hepatocellular carcinoma
Cholangiocarcinoms

Benign:
Hemangiomas
Adenomas

Question 323

Define hepatocellular carcinoma

Answer 323

Primary hepatocyte neoplasia. Accounts for 90% of primary liver cancers.

Question 324

Epidemiology of Hepatocellular carcinoma

Answer 324

• Common in China and Africa
• 2% prevalence in UK
• M>F

Question 325

Aetiology of Hepatocellular carcinoma

Answer 325

• HBV - leading cause worldwide especially, if high viral load
• HCV
• Autoimmune hepatitis
• Cirrhosis
• NAFLD
• Aflatoxin
• Clonorchis sinensis
• Anabolic steroids

Question 326

RF for Hepatocellular carcinoma

Answer 326

• HBV
• HCV
• Cirrhosis

Question 327

pathophysiology of hepatocellular carcinoma

Answer 327

• Tumour is either single or occurs as multiple nodules throughout the liver
• Consists of cells resembling hepatocytes
• It can metastasise via the hepatic or portal veins to the lymph nodes, bones
  and lungs

Question 328

Signs of Hepatocellular carcinoma

Answer 328

• Signs
  
  • Palpation - enlarged, irregular, tender liver may be felt
  • Signs of chronic liver disease
  • Signs of decompensation - jaundice (will appear late), ascites
  • Listen for bruit - murmur over the liver

Question 329

Symptoms of hepatocellular carcinoma

Answer 329

• Symptoms
  
  • Fever
  • Malaise
  • Fatigue
  • Loss of appetite
  • Weight loss
  • RUQ pain
  • Jaundice
  • Ascites
  • Haemobilia - bleeding into biliary tree

Question 330

Investigations for hepatocellular carcinoma

Answer 330

• CT - to identify HCC but hard to confirm diagnosis if the lesion is less than 1cm. Usually used to confirm diagnosis if lesion is large enough
• Ultrasound - to identify lesions
• MRI - to distinguish between benign and malignant
• Biopsy - used less now due to potential seeding of tumour along biopsy tract and
  since imaging is better
• Blood: FBC, clotting, LFT, hepatitis serology, serum alpha-fetoprotein may be raised

Question 331

Management for hepatocellular carcinoma

Answer 331

• Resect solitary tumours
• Liver transplant
• Percutaneous ablation (radiowaves destroy tumour), tumour embolisation (TACE - to restrict tumours blood supply) and sorafenib (kinase inhibitor) are also treatment options

Question 332

Prevention of hepatocellular carcinoma

Answer 332

• HBV vaccination
• Don’t reuse needles
• Screen blood
• Reduce aflatoxin exposure
• MonitoringConsider monitoring in high risk patients e.g. patients with cirrhosis, chronic HBV in Africans or older Asians
  • AFP +/- ultrasound (6-monthly screen)

Question 333

Define Cholangiocarcinoma

Answer 333

Biliary tree cancer. Makes up 10% of the primary liver cancers.

Question 334

Aetiology of Cholangiocarcinoma

Answer 334

• Associated with infestation with parasitic worms (flukes) e.g. Clonorchis sinensis
• Primary sclerosing cholangitis
• Biliary cysts
• Caroli’s disease - genetic condition that causes the bile ducts in the liver to be wider than usual
• HBV
• HCV
• Diabetes mellitus
• N-nitroso toxins (carcinogenic)

Question 335

Rf for cholangiocarcinoma

Answer 335

• Inflammatory bowel disease
• HBV
• HCV
• Infection with parasitic worms (flukes)

Question 336

Pathophysiology for Cholangiocarcinoma

Answer 336

Usually slow-growing cancers. Most are distal extrahepatic or perihilar

Question 337

Signs and symtpoms of cholangiocarcinoma

Answer 337

• Signs
  
  • Palpation - enlarged, irregular, tender liver may be felt
  • Signs of chronic liver disease
  • Signs of decompensation - jaundice, ascites
  • Listen for bruit - murmur over the liver
• Symptoms
  
  • Fever
  • Weight loss
  • Abdominal pain +/- ascites
  • Malaise

Question 338

Investigations of cholangiocarcinoma

Answer 338

• CT and ultrasound - to identify lesions
• MRI - to distinguish between benign and malignant
• Biopsy - may achieve histological diagnosis
• ERCP
• Blood: FBC, clotting, LFT, hepatitis serology, serum alpha-fetoprotein may be raised, raised bilirubin, raised ALP

Question 339

Management of cholangiocarcinoma

Answer 339

• Surgery (not possible in 70% of patients at presentation)
  
  • e.g. major hepatectomy, extrahepatic bile duct excision and caudate lobe resection
• Purcutaneous stenting or ERCP - stenting of obstructed extrahepatic bililary tree improves QOL
• Liver transplantation

Question 340

Complications of cholangiocarcinoma

Answer 340

Post-op complications:

• Liver failure
• Bile leak
• GI bleeding

Question 341

Prognosis of cholangiocarcinoma

Answer 341

70% are inoperable at presentation. Those that are operable, around 76% recur.

5-yr survival post-op = 30%

Question 342

Give an overview of Hemangiomas

Answer 342

• Commonest benign tumour
• Usually small and single but can be multiple and large
• Often incidental finding on US or CT
• Don’t require treatment

Question 343

Give an overview of liver Adenomas

Answer 343

• Common
• Caused by anabolic steroids, oral contraceptive pill, pregnancy
• Can present with abdominal pain or intraperitoneal bleeding
• Only treat if symptomatic or >5cm

Question 344

Epidemiology of secondary liver tumours

Answer 344

• Most common liver tumour is secondary (metastatic tumour)
• Mainly from breast, bronchus and GI tract
• Secondary liver tumours are usually multiple and they signify advanced disease

Question 345

RF for Secondary liver tumours

Answer 345

Primary cancer elsewhere

Question 346

Clinical manifestations of secondary liver tumours

Answer 346

• Variable, depending on primary cancer
• Generic features include:
  
  • Weight loss
  • Malaise
  • Upper abdominal pain
  • Hepatomegaly +/- jaundice

Question 347

Investigations for secondary liver tumours

Answer 347

• Ultrasound is primary investigation
  
  • Use CT, MRI, marrow biopsy, CXR, mammography, colonoscopy etc to find primary cancer
• Bloods: present similar to primary liver tumours

Question 348

Management for secondary liver tumours

Answer 348

• Depends on site of the primary and the burden of liver metastases
• Removal of primary tumour and hepatic resection
• Small, solitary metastases may be amenable to resection
• Chemotherapy may be used - e.g. in lymphomas and germ cell tumours
• Palliative care

Question 349

Prognosis for secondary liver tumours

Answer 349

Varies with type and extent of primary tumour.

Prognosis is often <6 months.

Question 350

Define Pancreatic Adenocarcinoma

Answer 350

‘Pancreatic cancer’ refers to primary pancreatic ductal adenocarcinoma, which accounts for >85% of all pancreatic neoplasms. These adenocarcinomas usually affect the head of the pancreas, but sometimes the body and tail. Some are multifocal.

Question 351

Epidemiology of pancreatic adenocarcinoma

Answer 351

• In females in the UK, pancreatic cancer is the 9th most common cancer. In males in the UK, it is the 12th most common cancer.
• The estimated incidence of pancreatic cancer is 10 per 100,000 individuals
• 9000 deaths/ year in the UK.
• Most common at 65-75 years of age

Question 352

RF for pancreatic adenocarcinoma

Answer 352

• Male
• Family history
• Smoking
• Alcohol
• Obesity
• Diet high in red meat
• Diabetes: a risk factor and a potential consequence of pancreatic cancer
• Chronic pancreatitis
• Genetic: hereditary non-polyposis colorectal carcinoma, BRCA1 and BRCA2 mutations, Peutz-Jeghers syndrome
• Multiple endocrine neoplasia

Question 353

Pathophysiology of pancreatic adenocarcinoma

Answer 353

Pancreatic cancer develops from pre-invasive pancreatic intraepithelial neoplasia, which can eventually become an invasive ductal adenocarcinoma. Other precursor lesions include mucinous cystic and papillary mucinous neoplasms. Over 90% of cases carry a faulty K-RAS gene (a proto-oncogene), while more invasive subtypes tend to also carry CDKN2A (p16), p53 and SMAD4.

Most pancreatic cancers metastasise early and present late. 60% arise in pancreatic head, 25% in the body and 15% in tail.

Question 354

Signs and symptoms of pancreatic adenocarcinoma

Answer 354

• Positive Courvoisier’s sign: In the presence of painless obstructive jaundice, a palpable gallbladder isunlikelyto be due to gallstones
• Trousseau sign of malignancy: migratory thrombophlebitis (blood clots felt as small lumps under skin)
• Symptoms
  
  • Painless jaundice
  • Non-specific symptoms:
    
    • Epigastric or atypical back pain, anorexia, weight loss; these features are common
  • New-onset diabetes:
    
    • Thirst, polyuria, nocturia, weight loss
    • Due to the loss of endocrine function
  • Nausea and vomiting
  • Steatorrhoea: due to loss of exocrine function fats are not digested
  • Dark urine and pale stools: due to obstructive jaundice
  • Cancer related anorexia
  • Acute pancreatitis

Question 355

All investigations for pancreatic adenocarcinoma

Answer 355

• LFTs:likely an obstructive picture with raised ALP, GGT and bilirubin
• Coagulation profile:assess the synthetic function of the liver to determine the possibility of liver metastasis
• CA 19-9:will be raised but is non specific - so can be used to monitor disease progression but isnotdiagnostic.
  
  • Serum lipase and serum amylase may also be raised, but this is non-specific
• Abdominal ultrasound:first-line imaging (60-90% sensitivity) and if any suspicion proceed to CT. However, a normal ultrasound doesnotexclude cancer
• CT chest, abdomen and pelvis: investigation of choice and also useful in staging; CT pancreatic protocol is 97% diagnostic
• Other investigations to consider
  
  • PET CT:NICE recommend performing a PET scan if CT is inconclusive
  • Endoscopic ultrasound: used if CT is inconclusive and allows fine-needle aspiration. Useful at identifying small tumours
  • ERCP: used if CT is inconclusive and allows for biliary drainage at the same time as tissue sampling
  • MRCP:typically not required if the above tests are performed

Question 356

Management of localised pancreatic adenocarcinoma

Answer 356

• Localised tumour
  
  • Surgical resection:
    
    • Less than 20% are suitable for surgery at diagnosis
    • Whipple’s resection: pancreaticoduodenectomy for resectable lesions of the head of the pancreas. This removes the antrum of the stomach, proximal duodenum, head of the pancreas, common bile duct and gallbladder
    • Laparoscopic excision: easiest for tail lesions
  • Adjuvant chemotherapy: offered after surgery.
    
    • Neoadjuvant chemotherapy (before surgery to shrink tumour) may also be offered

Question 357

Management of locally advanced or metastatic adenocarcinoma

Answer 357

• Locally advanced or metastaticPalliative management:
  • ERCP with stenting: for symptomatic relief of obstructive jaundice in patients with unresectable and metastatic tumours
  • Chemotherapy/chemoradiotherapy: offered if patients are able to tolerate it
  • Management of pain: opiates or radiotherapy

Question 358

Complications of pancreatic adenocarcinoma

Answer 358

Cancer-related:

• Venous Thromboembolism (VTE):pancreatic adenocarcinoma is thrombogenic and patients are at increased risk of DVT and PE
• New-onset diabetes mellitus:reduced endocrine function due to cancer growth, as well as surgical resection
• Cholangitis:obstruction of biliary drainage due to a head of pancreas cancer predisposes to biliary tree infection

Surgery-related:

• Dumping syndrome: occurs when sugar moves too quickly into the small bowel
  
  • Early dumping syndrome:occurs 30 mins after a meal as fluid moves into the intestine due to the high osmotic load, resulting in dizziness and palpitations
  • Late dumping syndrome: occurs 2 hours after a meal. As glucose is rapidly absorbed in the intestine, this causes reactive hyperinsulinaemia and subsequent hypoglycaemia
• Peptic ulcer disease

Question 359

Prognosis for pancreatic adenocarcinoma

Answer 359

The overall 5-year survival is 5%. Even for the minority of patients suitable for surgical resection, the median survival ranges from 15 to 19 months, with a 5-year survival rate of only 20%. Metastatic disease is associated with a survival of 3 to 6 months.

Better prognosis if tumour <3cm, with no node involvement.

Question 360

Define ascites

Answer 360

Ascites is the accumulation of free fluid within the peritoneal cavity.

Physiologically, in men, no fluid should be present. In women, up to 20 mls may be considered normal depending on the timing of the menstrual cycle.

Ascites, like pleural fluid, can be broadly divided intotransudatesorexudates:

• Transudate: due to the ultrafiltration of plasma (i.e. removal of fluid). It does not contain large proteins and only few cells.
• Exudate: due to leakage of whole contents of plasma (i.e. fluid, cells and proteins). Largely due to an inflammatory process.

In ascites, rather than using the terms transudate and exudate, we refer toraised portal pressureornormal portal pressure

Question 361

Aetiology of ascites

Answer 361

• Malignancy e.g. abdominal cancers
• Infections, especially TB
• Low albumin - less ability to pull fluid back into intravascular space
• Pancreatitis
• Bowel obstruction
• Myxoedema

With portal hypertension

• Cirrhosis
• Congestive cardiac failure, pericarditis - due to raised pressure in vessels causing fluid to leak out
• Budd-Chiari syndrome
• Inferior vena cava or portal vein thrombus
• Risk Factors

Question 362

RF for ascites

Answer 362

• High sodium diet
• Hepatocellular carcinoma
• Splanchnic vein thrombosis resulting in portal hypertension

Question 363

Clinical manifestations of ascites

Answer 363

• Abdominal swelling
• Distended abdomen
• Fullness in the flank and shifting dullness
• Mild abdominal pain and discomfort
  
  • Severe pain may signal towards bacterial peritonitis
• Respiratory distress
• Difficulty eating
• Scratch marks on abdomen due to itching caused by jaundice
• Many patients also have peripheral oedema

Question 364

History for ascites

Answer 364

• How long has the swelling been there?
• Drugs?
• Weight loss?
• Story suggestive of any underlying cause?

Question 365

Examination for ascites

Answer 365

Percussion - demonstrating shifting dullness - percuss centrally to laterally until dull sound. Keep finger at dull spot and ask patient to lean to opposite side. If the dullness was fluid, it will have moved and the previously dull area will now be resonant

Question 366

Other tests for ascites

Answer 366

• Ascitic fluid tap - fluid sample for cytology, culture and albumin
  
  • Raised white cell count - indicative of bacterial peritonitis
  • Gram stain and culture
  • Cytology to find malignancy
  • Amylase to exclude pancreatic ascites
  • Protein levels - transudate (low protein, less bad), exudate (high protein, extremely bad) - refer to SAAG notes below
• Ultrasound

Question 367

What is SAAG

Answer 367

The serum ascites-albumin gradient (SAAG) is used to determine the cause of liver disease. It is used to determine whether the aetiology of ascites is from raised portal pressure (transudate) or normal portal pressure (exudate).

SAAG = serum albumin (g/dL or g/L) - ascitic fluid albumin (g/dL or g/L)

• High SAAG (>1.1 g/dL or >11 g/L): transudate
• Low SAAG (<1.1 g/dL or < 11g/L): exudate

Question 368

Management for ascites

Answer 368

• Treat underlying cause
  
  • e.g. antibiotics for SBP
• Reduce sodium to help liver and reduce fluid retention
• Increase renal sodium excretion. Diuretic of choice is spironolactone (potassium-sparing aldosterone antagonist)
• Drain fluid (paracentesis) - can drain 5 litres at a time
• Transjugular Intrahepatic Portosytemic Shunt (TIPS) - can be used for resistant ascites

Question 369

Complications for ascites

Answer 369

• Severe hypovolemia due to reaccumulation of ascites post-drainage
  
  • Intravascular replenishment needed prior to drainage to avoid this complication.

Question 370

Prognosis for ascites

Answer 370

10-20% survival 5 years from onset

Poor prognosis

Question 371

Physiology of the peritoneum

Answer 371

Consists of two parts:

Parietal:

• Covers the abdominal wall
• Somatic innervation
• Sensation is well localised

Visceral:

• On organs e.g. stomach, liver and colon
• Autonomic innervation
• Sensation is poorly localised

Peritoneal cavity is a closed sac lined by mesothelial cells; these produce surfactant, which acts as a lubricant within the peritoneal cavity.

The cavity contains < 100mL of serous fluid containing < 30g/L of protein (transudate)

The mesothelial cells lining the diaphragm have gaps that allow communication between the peritoneum and the diaphragmatic lymphatics

Around 1/3rd of fluid drains through these lymphatics, the remainder through the parietal peritoneum

These mechanisms allow particulate matter to be removed rapidly from the peritoneal cavity

Question 372

Define peritonitis

Answer 372

Inflammation of the peritoneum

Question 373

Aetiology of peritonitis

Answer 373

• Primary peritonitis - inflammation caused by spontaneous bacterial peritonitis. This is the most common type of peritonitis
  
  • e.g. E.coli, klebsiella, staphylococcus aureus
• Secondary peritonitis - caused by something else e.g. chemical such as, bile

Question 374

Pathophysiology of peritonitis

Answer 374

SBP is theorised to occur by two mechanisms:

• Direct spread:bacterial translocation across the bowel wall
• Haematogenous spread:bacteria enter ascites via the blood stream in the context of an immunosuppressed state

Question 375

Clinical manifestations of peritonitis

Answer 375

• PerforationCauses SUDDEN ONSET with acute severe abdominal pain followed by general collapse and shock
• When peritonitis is secondary to inflammatory disease, the onset is less rapid with the initial features being those of the underlying disease
• Poorly localised (irritation of visceral peritoneum) then moving to one point on abdomen and becoming localised (when it begins to irritate the parietal peritoneum)
• Rigid abdomen
• Tenderness and guarding of abdomen
• Pain relieved by resting hands on abdomen - thereby stopping movement of peritoneum and thus pain
• Lying still - people with peritonitis want to stay still
• Prostration - lying stretched out on the ground

Question 376

General investigations for peritonitis

Answer 376

• Blood test:
  
  • To monitor/confirm infection - raised white cell count and CRP
  • Serum amylase to exclude acute pancreatitis
  • Human Chorionic Gonadotrophin (HCG):
    
    • Hormone secreted in pregnancy
    • Obviously there is abdominal pain in pregnancy
    • This test is to exclude pregnancy as cause
• Erect CXR - may see free air under diaphragm
• Abdominal X-ray to exclude bowel obstruction and foreign body as cause of abdominal pain
• CT abdomen to exclude ischaemia as cause of pain

Question 377

What further investigations would you do for spontaneous bacterial peritonitis (SBP)

Answer 377

• Ascitic tap - high white cell count
• Blood cultures

Question 378

Management for peritonitis

Answer 378

• ABC (airways, breathing, circulation)
• Insertion of nasogastric tube
• IV fluids
• Treat underlying cause and treat early
  
  • Broad spectrum antibiotics e.g. cephalosporin. Following an episode of SBP, patients require prophylactic oral antibiotics e.g. rifaximin.
  • Surgery for secondary peritonitis:
    
    • Laparotomy - perform a full exploration and lavage (clean) of the peritoneum.
    • Specific treatment of the underlying condition

Question 379

Complications of peritonitis

Answer 379

• Delay in treatment can produce toxaemia and septicaemia which may lead to multi-organ failure
• Local abscess formation can occur and should be suspected if a patient continues to remain unwell post-op, with a swinging fever, high white cell count and continuing pain
• Abscesses are commonly pelvic or subphrenic and can be localised using ultrasound and CT
• Kidney failure
• Paralytic ileus:
  
  • Peristaltic waves in colon stop leading to fluid stagnation causing distended gut and bloating which puts pressure on stomach and interferes with diaphragm and thus breathing - causes patient to breathe less deeply which promotes infection as bacteria can remain deep in lungs as they are not exhaled

Question 380

Prognosis for peritonitis

Answer 380

The one year survival following an episode of SBP is 30-50%

Question 381

Define Hernia

Answer 381

A hernia occurs when an internal part of the body pushes through a weakness in the muscle or surrounding tissue wall. A hernia usually develops between your chest and hips. In many cases, it causes no or very few symptoms, although you may notice a swelling or lump in your tummy (abdomen) or groin.

Question 382

Classification of hernias

Answer 382

• Irreducible - contents cannot be pushed back into place
• Obstructed - bowel contents cannot pass as the intestine is obstructed
• Strangulated - ischaemia occurs as blood supply of the sac is cut off - this requires urgent surgery.
• Incarceration - contents of the hernial sac are stuck inside by adhesions

Question 383

What are the types of hernia

Answer 383

Inguinal, Femoral, Umbilical, Incisional, Epigastric, Hiatal

Question 384

Define inguinal hernia

Answer 384

The protrusion of abdominal contents through the inguinal canal

Question 385

Epidemiology of inguinal hernia

Answer 385

• Commonest type of hernia in both men and women. Account for 70% of all abdominal hernias
• M>F
• Most common in men >40 years

Question 386

Aetiology of inguinal hernia

Answer 386

• Inherent or acquired weakness at site
• Increased abdominal pressure

Question 387

RF for inguinal hernia

Answer 387

• Male
• Chronic cough
• Constipation
• Urinary obstruction
• Heavy lifting
• Ascites
• Past abdominal surgery

Question 388

Pathophysiology of inguinal hernias

Answer 388

The inguinal canal is a passage that extended medially and inferiorly, through the inferior part of the abdominal wall. It acts as a pathway by which structures can pass from the abdominal wall to the external genatalia, and are a potential site of weakness, and so are prone to hernias.

Inguinal hernias pass through the internal inguinal ring and, if large, out through the external ring. They present above and medial to the pubic tubercle.

2 types of inguinal hernia: direct and indirect (more common)

Direct hernia: hernia protrudes through the posterior wall of the inguinal canal.

• Less common (20%)
• Direct inguinal hernias protrude through acquired defects in the posterior wall of the inguinal canal. This occurs in an area termed Hesselbach’s triangle.
• Rarely strangulate
• Reduce easily

Indirect hernia: hernia protrudes through the deep inguinal ring and into the inguinal canal

• More common (80%)
• Indirect inguinal hernias exit the abdominal wall via the deep inguinal ring. They may pass through the entirety of the inguinal canal and protrude anywhere along its length or into the corresponding testicle. If large enough, they protrude out through the superficial inguinal ring
• Lateral to the inferior epigastric artery
• Can strangulate

Question 389

Clinical manifestations of inguinal hernias

Answer 389

• Bulging associated with coughing or straining (bowel movement, heavy lifting)
• Appearance of lump
• Rarely painful
  
  • If painful then indicates strangulation
• Patient can usually reduce the hernia themselves

Question 390

Investigations for inguinal hernias

Answer 390

Look for lump and previous scars, check for cough impulse (swelling expands when coughing) - compare to the other side.

Examine external genitalia

Question 391

Differentials for inguinal hernias

Answer 391

Femoral hernia

Epididymitis

Testicular torsion

Groin abscess

Aneurysm

Hydrocele

Undescended testes

Question 392

Management for inguinal hernias

Answer 392

• Medical:
  
  • Use of truss to contain and prevent further progression of hernia
• Surgical: indicated if patient is very symptomatic
  
  • Pre-op: diet and stop smoking
  • Three types:
    
    • Herniotomy:contents reduced and hernial sac removed. Typically used in children with congenital patent processus vaginalis.
    • Herniorrhaphy:combines a herniotomy with repair of the posterior inguinal wall.
    • Hernioplasty:combines a herniotomy with the insertion of a mesh to reinforce the posterior inguinal wall
  • Can be open repair or laparoscopic (total extra-peritoneal (TEP) or transabdominal pre-peritoneal (TAPP) repair)

Question 393

Define femoral hernias

Answer 393

Bowel enters the femoral canal (presenting as a mass in upper medial thigh) or above the inguinal ligament (points down the leg)

Likely to be irreducible and to strangulate due to the rigidity of the canal’s borders

Question 394

Epidemiology of femoral hernias

Answer 394

• Occur more often in females
• More common in middle-age and elderly

Question 395

Investigations for femoral hernias

Answer 395

The neck of the hernia is felt inferior and lateral to the pubic tubercle

Question 396

Differential diagnosis for femoral hernia

Answer 396

• Inguinal hernia
• Saphena varix (dilation of saphenous vein at junction of femoral vein in groin)
• Enlarged cloquet’s node
• Lipoma
• Femoral artery aneurysm
• Psoas abscess

Question 397

Management for femoral hernia

Answer 397

• Surgical repair
  
  • Herniotomy - ligation and excision of the sac
  • Herniorrhaphy - repair of the hernial defect

Question 398

Define umbilical hernia

Answer 398

A type of paediatric hernia affecting 3% of life births.

Question 399

Pathophysiology of umbilical hernia

Answer 399

A result of a persistent defect in the transversalis fascia

Question 400

Management for umbilical hernia

Answer 400

Rarely needed, most resolve by the age of 3.

Question 401

Define incisional hernia

Answer 401

Occurs when tissue protrudes through a surgical scar that is weak

They are a complication of abdominal surgery but can occur anywhere where there is an incision and follows a breakdown of muscle closure after surgery

Question 402

RF for incisional hernia

Answer 402

• Emergency surgery
• Wound infection post op
• Persistent coughing and heavy lifting
• Poor nutrition

Question 403

Management of incisional hernia

Answer 403

• Repair is more difficult in those that are obese
• Mesh repair - reduced recurrence but associated with high levels of infection

Question 404

Define epigastric hernia

Answer 404

Pass through the linea alba above the umbilicus

Question 405

Define hiatal hernia

Answer 405

A condition where part of the stomach pushes up into the lower chest through a weakness in the diaphragm.

2 subtypes:

• Sliding hiatus hernia
• Paraoesophageal hernia (rolling hiatus hernia)

Question 406

Epidemiology of hiatal hernia

Answer 406

30% of patients are above 50, especially obese women

Question 407

Pathophysiology of hiatal hernia

Answer 407

Sliding hiatus hernia (80%) - the gastrooesophageal junction slides up into the chest. Acid reflux can occur as the lower oesophageal sphincter becomes less competent.

Paraoesophageal hernia (20%) - the gastrooesophageal junction remains in the abdomen but the bulge of stomach herniates up into the chest alongside the oesophagus. GORD is less common as the gastrooesophageal junction remains intact

Question 408

Clinical manifestations of hiatal hernia

Answer 408

• Small hernias - asymptomatic
• Large hernias - GORD

Question 409

Investigations of hiatal hernia

Answer 409

• Upper GI endoscopy - to visualise the mucosa, but cannot exclude hiatus hernia
• Barium swallow to confirm diagnosis

Question 410

Management of hiatal hernia

Answer 410

• Weight loss
• Treatment of GORD
• Surgical treatment, if:
  
  • High risk of strangulation
  • Intractable symptoms despite medical therapy
  • Complications

Question 411

Define paracetamol overdose

Answer 411

A toxic overdose is defined as ingestion of paracetamol >75mg/kg.

12g/ 24 tablets or 150mg/kg in adults may be fatal

Question 412

Epidemiology of paracetamol overdose

Answer 412

Paracetamol is the most common drug in overdose, associated with approximately 100 to 200 deaths per year in the UK

Question 413

RF/aetiology of paracetamol overdose

Answer 413

• Depression or history of self-harm
• Glutathione deficiency
• Alcoholism,malnutrition and anorexia: key risk factors for hepatotoxicity
• P450 inducers: increased risk of hepatotoxicity due to facilitation of paracetamol metabolism and NAPQI production
  
  • Examples include rifampicin, carbamazepine, phenytoin, St John’s Wort and long-term alcohol excess
  • Surprisingly, acute alcohol intake may actually be protective against hepatoxicity

Question 414

Pathophysiology of paracetamol overdose

Answer 414

Paracetamol is converted to a number of metabolites, most of which are non-toxic. Predominantly metabolised via a Phase II reaction - conjugated with glucuronic acid & sulphate. A small proportion is metabolised by the P450 system to the toxic metabolite known as N-acetyl-p-benzoquinone imine (NAPQI), which is a mitochondrial poison. It is typically detoxified by conjugation with glutathione. In the case of a paracetamol overdose, as the production of NAPQI increases, glutathione stores become depleted, leaving NAPQI to remain unconjugated and resulting in hepatocellular damage.

Acute liver failure is a feared complication of paracetamol overdose.

Question 415

Signs of paracetamol overdose

Answer 415

• Jaundice
• Encephalopathy - reduced GCS - consciousness
• Tachycardia/ hypotension
• Evidence of self-harm

Question 416

Symptoms of paracetamol overdose

Answer 416

• Abdominal pain
• Right upper quadrant pain
• Nausea or vomiting
• Confusion or coma

Question 417

Risk assessment for paracetamol overdose

Answer 417

• Date of ingestion: is there a delay in presentation?
• Timing of ingestion: single overdose or staggered
• Time since last ingestion(even staggered)
• Weight: if >110 kg, used 110 kg as the maximum weight for calculations.
• Pregnancy: use pre-pregnancy weight to determine toxicity and current weight for treatment
• Total amount ingested(mg/kg)
• Current suicidal risk: consider a registered mental health nurse (RMN) to stay with the patient

Question 418

Investigations for paracetamol overdose

Answer 418

• Serum paracetamol:levels should be measured at 4 hours post-ingestion. If presenting after 4 hours of ingestion, take levels immediately
• LFTs:deranged liver function and rising INR
• Clotting screen:PT and APTT prolonged in hepatocellular damage
• U&E:severe toxicity results in renal failure
• Arterial blood gas:severe toxicity results in a lactic acidosis

Question 419

1st line management of paracetamol overdose

Answer 419

• Activated charcoal:reduces intestinal absorption
  
  • Administered if the patient presentswithin 1 hourof ingestion
• N-acetylcysteine (NAC):**replenishes glutathione stores which bind NAPQI, the toxic metabolite
  
  • NAC is given in the following instances:
    
    • Timed plasma paracetamol level on or above treatment line(see nomogram)
    • Doubt over ingestion time: regardless of the paracetamol concentration
    • Staggered overdose: when all the tablets arenottaken within 1 hour
  • NAC was previously infused over 15 minutes but is now infused over1 hourto avoid side effects. Second infusion is over 4 hours.
  • Next day do INR, U&E, LFT. If INR rising, continue NAC.
  • Side effect: rash. Give chlorphenamine

Question 420

What is a nomogram

Answer 420

If the paracetamol concentration lies on or above the treatment line, NAC should be administered.

When there is doubt regarding management, the National Poisons Information Service/TOXBASE should be consulted.

Question 421

Other management for paracetamol overdose

Answer 421

• Liver transplantation:indicated as per the King’s College Criteria if arterial pH < 7.3 after 24 hours of ingestionOR all three of the followingare present:
  
  • Prothrombin time > 100 seconds
  • Creatinine > 300 µmol/l
  • Grade III or IV encephalopathy
• Psychiatric input for deliberate overdoses

Question 422

Complications of paracetamol overdose

Answer 422

• Acute liver failure:evidence of liver failure may warrant urgent liver transplantation, as per the King’s College Criteria
• Acute kidney injury - due to acute tubular necrosis occurs in 25% of patients who have severe hepatic damage
• Anaphylactoid reaction: NAC may cause ananaphylactoid reactiondue to non-IgE mediated mast cell degranulation (10-50% of patients). It often occurs with lower paracetamol ingestions after the first bag of NAC and is usually managed by pausing the infusion and restarting at a reduced rate

Question 423

Prognosis for paracetamol overdose

Answer 423

Hepatic regeneration can take place, whereby function is normalised rapidly. However, patients with staggered overdose or delayed presentation have a higher risk of liver failure and mortality.