Liver Flashcards
What organs are retroperitoneal
SAD PUCKER
S - Suprarenal (adrenal) glands
A - Aorta
D - Duodenum
P - Pancreas
U - Ureter
C - Colon (descending, ascending)
K - Kidneys
E - Oesophagus (lower 2/3)
R - Rectum
Functions of the liver
- Protein synthesis (albumin, clotting factors)
- Glucose and fat metabolism
- Defence against infection (reticuloendothelial system)
- Detoxification and excretion (ammonia, bilirubin, drugs/hormones)
Describe the blood flow around the liver
Blood enters via hepatic artery (oxygenated blood) and portal vein (deoxygenated blood from intestine containing nutrients), which lie together in lobules with a bile duct. Blood flows into sinusoids, bathing liver cells, before exiting via central hepatic vein. Liver cells within lobule can be divided into zones 1 to 3, receiving progressively less oxygenated blood
End points of liver injury (in acute and chronic)
Acute
- Recovery
- Liver failure
- Progression to Chronic
Chronic
- Recovery
- Cirrhosis
- Liver failure
- Varices
- Hepatoma
What are cellular consequences of acute and chronic liver failure
Acute - damage to and loss of cells, causing necrosis or apoptosis
Chronic - Fibrosis (called cirrhosis when severe)
Define cholestasis
Any condition where bile flow is blocked
What tests are used to assess liver function? (7)
- AST
- ALT
- ALP
- GGT
- Bilirubin
- Albumin
- Prothrombin time (and INR)
What do the LFTs help distinguish
AST, ALT, ALP, GGT differentiate hepatocellular damage (AST, ALT) and cholestasis (ALP, GGT)
Bilirubin, albumin, PT assess liver’s synthetic function
What does ALT stand for and show
alanine transaminase
Marker of hepatocellular damage; found in high concentrations within hepatocytes
What does ALP stand for and show
Alkaline phosphatase
Particularly concentrated in liver, bone and bile ducts. Shows liver pathology in response to cholestasis.
Also raised in bone pathology especially pagets and bone cancer
What does GGT stand for and show?
gamma glutamyl transferase
Raised GGT suggests biliary epithelial damage and bile flow obstruction. Can be used with ALP to suggest cholestasis.
How are ALT and ALP compared to find pathology
> 10x ALT, <3x ALP suggests predominantly hepatocellular injury
<10x ALT, >3x ALP suggests cholestasis
How is the AST/ALT Ratio used?
AST/ALT ratio
- ALT>AST - Chronic liver disease
- AST>ALT - Acute alcoholic hepatitis or cirrhosis
What blood test is a marker of pancreatitis
Serum amylase and lipase.
Lipase has a longer half life and is more specific, but takes longer to show as raised.
Define acute liver failure with 3 characteristic signs
Severe acute liver injury with impaired function and altered mental status in patient WITHOUT existing liver disease or cirrhosis
Jaundice
Coagulopathy (INR>1.5!!!!)
Hepatic encephalopathy
Causes of Acute Liver Failure
Drugs
- Paracetamol overdose
- Isonazid
- Alcohol
Infection
- Hepatitis A and B
- EBV
- CMV
- Herpes simplex virus
Vascular
- Veno-occlusive disease
- Budd-Chiari syndrome
- Autoimmune hepatitis
- Metabolic conditions (Wilson’s)
- Cancer
- Fatty liver of pregnancy
- PBC/PSC
Pathophysiology of acute liver failure
Depends on underlying cause
- Massive hepatocyte necrosis/apoptosis.
- Causes jaundice, coagulopathy (INR>1.5), hepatic encephalopathy (ammonia builds up in blood, travels to brain, clearance causes cerebral oedema)
- HE usually within 8-28 days of noticing jaundice but can be up to 28
Grading system for Hepatic Encephalopathy
West Haven criteria
1 - Change in behaviour with minimal change in consciousness
2 - Gross disorientation, drowsiness, asterixis, inappropriate behaviour
3 - Marked confusion, speech problems, incoherent speech, rousable to verbal stimuli
4 - Comatose, no response to stimuli
Signs/symptoms of Acute liver failure
- Jaundice
- Coagulopathy
- Hepatic Encephalopathy
Nausea, confusion, asterixis, abdominal pain
Investigations in Acute liver failure
- Serum bilirubin (high), albumin (low), prothrombin time/INR (raised)
- Serum transaminases (AST/ALT) suggest hepatocellular pathology
Others (to find cause)
- Abdominal US with dopper can be used to find vaso-occlusion
- ABG/paracetamol levels may indicate paracetamol overdose
- Blood culture to rule out infection
- EEG to grade HE
- Coagulation
- Lipase/amylase
- Serum ammonia
Management of acute liver failure
Raise head of bed, tracheal intubation and NG tube
Treat underlying cause/complications: - intracranial pressure - Mannitol IV
HE - Lactulose (NH3+ excretion)
Haemorrhage/bleeding (vit k)
Paracetamol overdose - N acetylcysteine
Complications of acute liver failure
Progression to chronic (Ascites, varices, oedema)
Bleeding
Hepatic Encephalopathy (confusion, coma, mood/behaviour change)
Pathophysiology of paracetamol overdose
- Paracetamol usually metabolised by liver, but small amount metabolised by cytochrome P450 system
- Toxic intermediate of p450 pathway (N-acetyl-p-benzoquinone imine (NAPQI)) is normally detoxified by conjugation with glutathione, when all glutathione used up, toxic intermediate remains and damages hepatocytes.
Treatment of paracetamol overdose
- N-acetylcysteine (replenishes glutathione stores, which bind to NAPQI)
or
- Activated charcoal if patient presents within 1 hour of ingestion
Define chronic liver failure
Repeated liver insults over at least 6 months causing progressive liver dysfunction, resulting in inflammation, fibrosis and cirrhosis.
Causes of chronic liver failure
- Alcohol (ALD)
- Viral (Hepatitis B,C)
- Inherited causes (A1 antitrypsin deficiency, Wilson’s, hereditary haemochromatosis)
- Autoimmune hepatitis
- PBC/PSC
- Budd-Chiari syndrome
- NAFLD
Pathophysiology of chronic liver disease
Repeat injury over time cause inflammation (hepatitis) -> fatty deposits (steatosis) -> scarring (fibrosis).
Normal liver replaced by fibrotic tissue and regenerative nodules.
Can be compensated (asymptomatic) or decompensated
Pathophysiology of chronic liver disease
Repeat injury over time cause inflammation (hepatitis) -> fatty deposits (steatosis) -> fibrosis/cirrhosis (normal hepatic tissue replaced by fibrotic tissue and regenerative nodules).
Liver cirrhosis can be compensated (asymptomatic, normal function) or decompensated (multiple complications/dysfunctions of liver)
Signs of decompensated liver disease
- Coagulopathy
- Jaundice
- Encephalopathy
- Ascites
- GI bleeding
- Varices
- Easy bruising
Chronic liver disease signs and symptoms (8)
- Spider naevi
- Splenomegaly
- Caput medusae (distended paraumbilical veins due to portal HTN)
- Dupuytren’s contracture (thickening of palmar fascia, causing fixed flexion of MCP)
- Ascites
- Palmar erythema
- Gynaecomastia and testicular atrophy
- Asterixis (flapping tremor)
Investigations in chronic liver disease
Same as acute
- LFT AST ALT Raised (ALT>AST - Chronic liver disease)
- Ultrasound
- CT more detailed, good for secondary findings (MRI best, but most expensive)
- Liver biopsy to check extent of CLD
- Ascitic tap
Management of Chronic liver disease
Treat underlying pathology and complications
HE - Lactulose
Ascites - Aldosterone antagonist (Spironolactone)
GI bleed (beta blocker to reduce portal HTN, Endoscopic variceal band litigation)
SBP - Antibiotics
Prevent further disease by reducing risk factor
What are the 2 types of liver cirrhosis
Micronodular
- <3mm with uniform involvement of liver (alcohol or biliary disease cause)
Macronodular
- Varying sizes, normal acini, can be seen in larger nodules
- Caused by viral hepatitis
Define liver cirrhosis
Final stage of any liver disease. Normal liver architecture converted to regenerative nodules, separated by fibrous septa, with a loss of lobular architecture
Characteristic biopsy findings of cirrhotic liver
Regenerating nodules
Wide fibrous septa
Loss of lobular architecture
What is the cell behind liver cirrhosis and how does it do this?
Apoptosis/necrosis activates stellate cells, which release cytokines that attract neutrophils and macrophages, causing further inflammation and fibrosis. Stellate cells become myofibroblasts which lead to collagen deposition.
Signs/symptoms of liver cirrhosis (10)
- Jaundice
- Hepatomegaly
- Splenomegaly
- Spider naevi
- Palmar erythema
- Clubbing
- Ascites
- Leuconychia (hypoalbuminemia)
- Xanthelasma (cholesterol deposits around eyes)
- Caput medusae (cluster of swollen veins in abdomen)
What will ultrasound and MRI show in cirrhosis
US - Hepatomegaly, splenomegaly, ascites
MRI - Increased caudate lobe size, right posterior hepatic notch suggests alcoholic pathology
Treatment of pruritus
Colestyramine
Lifestyle advice in liver cirrhosis
Alcohol abstinence
Avoid NSAID
Good nutrition
Exercise
Complications of liver cirrhosis
- Coagulopathy
- Encephalopathy
- Hypoalbuminaemia (Oedema/Ascites)
- HCC!!!
- AKI
- SBP
What scoring systems are used in cirrhosis
Child-Pugh score (Encephalopathy, Ascites, Bilirubin/Albumin, INR) (severity of long term disease)
MELD score (model for end stage liver disease, indicator for transplant necessity)
Alcohol units calculation
(Alcohol by volume * vol(mL)) / 1000
Define alcoholic liver disease
3 stage liver disease caused by excessive alcohol drinking. Leads to steatosis, hepatitis and eventually cirrhosis.
Pathophysiology of Alcoholic liver disease
Alcohol is metabolised in the liver to acetaldehyde by 3 pathways (alcohol dehydrogenase, CYP2E1, Catalase). This causes an increase in NADH, whilst decreasing NAD+, so more fatty acid synthesis occurs, but less oxidation ∴ hepatic fatty acids accumulate (steatosis - reversible).
CYP2E1 pathway generates free radicals which can damage hepatic DNA and proteins.
Acetaldehyde binds to liver macromolecules, forming adducts. These are attacked by immune system causing inflammation and hepatomegaly (hepatitis - reversible). Mallory bodies and giant mitochondria are visible histologically.
Damaged liver leaks AST/ALT
As cells die, scarring occurs around central vein of liver (perivenular fibrosis). This causes irreversible cirrhosis
Signs/symptoms of Alcoholic liver disease
Early stages- little/no symptoms, worse as time goes on.
Chronic liver failure + alcohol dependency/withdrawal symptoms as time goes on.
- Hepatomegaly
- Abdominal pain
- Dupuytren’s contracture
- Asterixis
- Palmar erythema
- Clubbing
- Spider naevi
- Hepatic encephalopahty
- Caput medusae
- Easy bruising
Signs of liver failure on hands
- Dupuytren’s contracture (fingers bend towards palm)
- Clubbing
- Palmar erythema
- Asterixis
Name as many signs of liver failure as possible
- Hepatomegaly
- Abdominal pain
- Dupuytren’s contracture
- Asterixis
- Palmar erythema
- Clubbing
- Spider naevi
- Hepatic encephalopahty
- Caput medusae
- Bruising
- Pruritus
- Weight loss
- Fever (cirrhosis)
- Haematemesis
- Splenomegaly
- Jaundice
Investigations in alcoholic liver disease
AST/ALT - high due to leakage from damaged liver
Ultrasound or CT - fatty liver
Liver biopsy - Grade fibrosis. Would see mallory bodies, neutrophil infiltrates, giant macrophages, increased fat cells, necrosis etc.
Management of Alcoholic liver disease
1st - Stop alcohol intake. Join support groups, take Chlordiazepoxide (benzodiazepine) - aids alcohol withdrawal
- Give vitamin B1 (thiamine) IV. Prevent Wernicke’s Encephalopathy and Korsakoff’s syndrome. (confusion, oculomotor disturbance, memory impairment, behaviour change)
- Short term steroids for hepatitis
Lifestyle advice
- Lose weight
- Stop smoking
- Increase vit K and B1
- High protein diet
- Liver transplant if severe
Severe complication of alcohol withdrawal with treatment
Delirium Tremens (delusions, hallucinations, tremor, tachycardia, ataxia, arrhythmia). Lorazepam used to treat (rapid acting benzodiazepine)
What can long term alcohol usage cause. How is this caused and how is it treated
Thiamine (vit B1) is poorly absorbed in presence of alcohol. Can cause Wernicke’s Encephalopathy or Wernicke-Korsakoff syndrome
IV thiamine is therefore needed in patients with alcoholism
Complications of alcoholic liver disease
Pancreatitis
Ascites
HCC
Wernicke Korsakoff syndrome
Hepatic encephalopathy
Define Wernickes encephalopathy
Thiamine (vitamin b1) deficiency causing a neurological emergency
Pathophysiology of Wernickes encephalopathy
And what happens if brainstem, cerebellum, medulla affected
Alcohol abuse inhibits thiamine;
- Blocks phosphorylation of thiamine
- Reduces gene expression for thiamine transporter 1
- Fatty liver prevents thiamine storage.
Causes haemorrhage and necrosis of mammillary bodies of limbic system (memory)
Deficiency impairs glucose glucose metabolism.
- In brainstem, face/eyes affected
- In cerebellum, movement/ balance
- In medulla, heartrate/breathing
Wernicke’s is acute and reversible, but can progress to chronic, irreversible Wernicke-Korsakoff syndrome.
Signs/symptoms of Wernickes/Korsakoff syndromes
Wernicke’s - Ophthalmoplegia, nystagmus (rapid side to side eye movements), Ataxia/unsteady gait, confusion, apathy, arrhythmia
Korsakoff - Limbic system (memory) impairment
- Anterograde and retrograde amnesia
- Confabulation (stories to fill gaps in memory which they believe)
- Behavioural changes
Treatment and complications of Wernickes/Korsakoffs
Treatment - IV thiamine, given with glucose if hypoglycaemic. Thiamine first as without thiamine pyrophosphatase, glucose becomes lactic acid -> metabolic acidosis
Complications
- Metabolic acidosis
- Seizures
- Spastic paraparesis
- Coma
- Death
NAFLD Definition with causes
Non Alcoholic Fatty Liver disease. Deposition of fat in liver that cannot be attributed to alcohol or viral cause.
Steatosis > Steatohepatitis > Fibrosis > Cirrhosis
Caused by insulin resistance and Metabolic syndrome
- Diabetes
- HTN
- Obesity
- Hyperlipidaemia
NAFLD pathophysiology
- Insulin resistance means receptors on hepatocytes become less responsive. Liver increases fat storage and decreases fatty acid oxidation. Fat droplets form in hepatocytes, swelling hepatocytes. Liver appears large, soft, yellow, fat, greasy (Steatosis)
- Unsaturated fatty acids vulnerable to free radicals, causing fatty acid radical formation, which damage lipid membrane causing inflammation (Steatohepatitis)
- Stellate cells lay down fibrous tissue (fibrosis), when architecture changes this becomes cirrhosis.
NAFLD signs/symptoms and investigations
Usually asymptomatic and found by accident. To be suspected in T2DM, obese, deranged LFT.
Signs of liver failure if severe.
LFT - Deranged LFT. (ALT>AST, high bilirubin)
FBC - anaemia, low platelets)
USS/MRI - show enlarged fatty liver.
Liver biopsy GOLD
Management of NAFLD
1st - Diet and exercise to reduce risk factor
Vitamin E supplements (Vit E clears free radicals)
How does Liver failure cause it’s signs
- 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)
Hepatic encephalopathy definition and pathophysiology
Liver failure as a result of decompensated chronic liver disease.
Ammonia is a by product of gut bacteria, and is cleared by liver. Ammonia builds and goes to brain. Ammonia is neurotoxic. Astrocytes attempt to clear ammonia but cause a build up in glutamine, causing an osmotic shift of fluid into cells -> Oedema -> brain damage.
Signs/symptoms of hepatic encephalopathy
Mood - Euphoria, depression, anxiety, confusion
Sleep - Insomnia, hypersomnia
Motor disturbance - Asterixis, ataxia, bradykinesia, hypokinesia, tremor
Can lead to coma, hyperreflexia, nystagmus
Investigations and treatment of hepatic encephalopathy
EEG
Serum ammonia
Head CT or MRI
Other investigations to check liver disease/ rule out neuro pathology
Supportive (IV fluid)
Lactulose (remove ammonia)
Rifaxamin (antibiotic) - prophylaxis
Define jaundice with 3 types
Raised serum bilirubin causing yellowing of skin and eyes. AKA icterus.
Pre hepatic - Increased unconjugated bilirubin, usually due to increased haemolysis.
- Normal urine and stools
Hepatic - Uncon/conjugated bilirubin. Pathology of liver means hepatocytes cant take up, metabolise or excrete bilirubin.
- Dark/normal urine, normal stools
Post hepatic - Conjugated bilirubin. Due to obstruction in biliary system.
- Dark urine, pale stools.
Why is urine darkened and why are stools paled as more bilirubin becomes conjugated?
Conjugated bilirubin can be excreted in urine (water soluble), unconjugated can’t. Hence, dark urine in post hepatic (conjugated bilirubin) or intrahepatic (mixed), but normal in pre hepatic (unconjugated)
In an obstructive jaundice, less stercobilin (which normally gives it colour) goes into GI tract and stools, so they go pale.
Causes of pre hepatic jaundice
Due to increased haemolysis.
- Sickle cell
- G6PD deficiency
- Hereditary spherocytosis
- Thalassaemia
- Malaria
- Autoimmune haemolytic anaemia
Causes of hepatic jaundice
HCC
ALD/NAFLD
Hepatitis
Hepatotoxic drugs (rifampicin)
Gilbert syndrome
Causes of post hepatic jaundice
Biliary tree pathology/obstruction
- Pancreatic cancer
- Cholelithiasis
- PBC/PSC
- Cholangiocarcinoma
- Drug induced cholestasis
- Pancreatitis
What symptoms usually accompany jaundice?
Itching!
Dark urine/pale stools if obstructive
Abdominal pain
Fatigue
Investigations in jaundice
1st line imaging: Abdominal ultrasound.
- LFT
- Urine bilirubin (- normally, high in dark urine) and urobilinogen (normally +ve, high in haemolysis, low in intra/post hepatic causes)
What is neonatal jaundice? + Complication of it
Normal. Fetal RBCs break down easily, releasing lots of unconjugated bilirubin. Resolves in 10 days. If not, can cause Kernicterus (brain damage due to raised bilirubin)
Define Ascites
Accumulation of free fluid in peritoneal cavity. (Up to 20ml normal in women). Causes are transudative (raised portal pressure causing ultrafiltration of plasma) or exudative (normal portal pressure, usually inflammatory process causing leakage of whole plasma contents (proteins/cells))
Exudate vs Transudate
Exudate - Inflammatory fluid release, due to changes in capillary permeability
- High protein
- Coagulates
- Contains inflammatory cells
Transudate - Non inflammatory (pressure gradients)
- Low protein
- Doesn’t coagulate
- No inflammatory cells
Causes of ascites
Causes of portal HTN (transudate)
- Cirrhosis (MOST COMMON)
- Portal vein thrombosis
- Sarcoidosis
- Schistosomiasis
- Budd-Chiari syndrome
- Constrictive pericarditis
- Hypoalbuminaemia (low protein in blood, less fluid pulled into vessel)
- Nephrotic syndrome
Exudate
- Cancer
- Sepsis
- TB
- Nephrotic syndrome
- Bowel obstruction
- Pancreatitis
- Myxoedema
Signs/symptoms of ascites
- Abdominal swelling
- Distended abdomen
- Shifting percussive dullness
- Fullness/fluid in flanks
- Respiratory distress
- Peripheral oedema
Signs on examination of ascites
Abdominal distension, shifting percussive dullness, fluid in flanks
How is ascites examination done
Percuss centrally -> laterally until dull sound. Keep finger at dull spot and have patient turn. If the dullness is due to fluid, dullness will have moved.
Investigations of ascites
1) Percussion/examination
2) Serum ascites, albumin gradient
- High SAAG - Transudate (high portal pressure)
- Low SAAG - Exudate (low portal pressure)
3) Abdominal ultrasound GOLD
4) Paracentesis/Ascitic tap - Fluid aspiration to send for microbiology etc
Management and main complication of ascites
Treat underlying cause (cirrhosis, heart failure etc)
- Spironolactone (diuretic)
- Paracentesis (fluid drainage)
Low sodium diet.
Ciprofloxacin as prophylaxis for SBP
Main possible complication of ascites
Spontaneous Bacterial Peritonitis (SBP)
- Infection of ascitic fluid and peritoneal lining. This is why fluid sent to microbiology
The types of viral hepatitis, RNA or DNA
Hep A - RNA, no envelope, acute
Hep B - DNA, enveloped
Hep C - RNA, enveloped
Hep D - RNA enveloped
Hep E - RNA no envelope
What Hep viruses are acute and what are chronic
Hep A - Acute
Hep B, C, D- Acute and Chronic
Hep E - Mainly acute, but can progress to chronic in immunosuppression
Modes of transmission for Hep viruses
A - Faeco-oral
B - Body fluids and blood
C - Blood
D - Body fluids and blood (only in those with Hep B)
E - Faeco-oral
Define Hepatitis A with epidemiology
Infection of liver, by non-enveloped single-stranded RNA virus of Picornavirus (Picornaviridae) family.
It is a notifiable disease with faeco-oral transmission and is endemic in areas with poor sanitation. Travel history to Africa or South America is usually key,
Pathophysiology of HAV
Replicates in liver and then is excreted in bile and faeces for ~2 weeks before onset of symptoms. Incubation period of 2-6 weeks. 4 phases:
1. Incubation period 2-6 weeks (usually 28-30 days)
2. Prodromal phase: Early disease, mild symptoms
3. Icteric phase- JAUNDICE + more severe symptoms. Most infectious right before jaundice onset.
4. Covalescent: Self limiting recovery, resulting in 100% immunity.
Signs/symptoms of HAV
Prodromal phase;
- Flu like. Fatigue, malaise, weakness, vomiting.
Icteric phase:
- Jaundice
- Rash
- Diarrhoea
- Dark urine/pale stools
- Hepatosplenomegaly
Investigations of HAV
ALT/AST high (ALT>AST)
Bilirubin high
Serology
- HAV IgM positive soon after symptoms develop and remains detectable for a few months. HAV IgG becomes positive 5-10 days after symptoms and is detectable lifelong.
- +IgM, +IgG = Acute Hep A
- -IgM, +IgG = Past infection or vaccination
Management of HAV
Disease management is supportive
All infectious hepatitis must be notified to UK Health Security Agency (UKHSA - Previously Public Health England)
Prophylactic Hep A vaccine if
- Travel to endemic area
- Chronic liver disease
- IV drug use
- Sexual MSM
Vaccine is inactivated viral vaccine.
Define Hepatitis B virus with mode of transmission and epidemiology
Enveloped dsDNA virus belonging to Hepadnaviridae family, can cause acute or chronic infection. Mode of transmission is through blood/bodily fluids;
- Unprotected sex
- Sharing needles/needlestick injury
- Perinatally
- Semen/saliva
Worldwide health problem
Hepatitis B protein products
HBsAg - Surface antigen on outer envelope. +ve in active infection. Takes up to 6 months to clear (carrier status until), and is replaced with HBsAb after.
HBeAg - Hep B ‘E’ Antigen secreted by infected cells. Marker of active replication and infection, increased E = Increased viral load/infectivity.
HbcAg - Hep B Core Antigen found on nucleocapsid in virus core. IgM antibodies of core antigen imply active infection. IgG imply past infection.
DNA polymerase and X protein also present
Hepatitis B antibodies
HBsAb - Surface antigen antibody. +ve in immunity (past infection or vaccination)
HBeAb - +ve, active disease phase over.
IgM HBcAb - Active acute infection (Decreases in chronic)
IgG HBcAb - +ve with +ve surface antigen = Active Chronic Infection
+ve with -ve surface antigen = Past infection
(Vaccination doesnt form defence against HbC)
Hep B pathophysiology
HBV enters hepatocytes, removes outer envelope and forms covalently closed circular DNA. cccDNA template for HBV proteins.
Usually (70%) subclinical with anicteric symptoms.
30% likely to go icteric.
Usually self limiting but can progress to chronic if HBsAg lingers >6 months (carrier status).
Chronic > Cirrhosis > HCC
- Most cases in children go chronic. NEED TRANSPLANT
Extra hepatic manifestations of HBV
Polyarteritis nodosa, glomerulonephritis, papular acrodermatitis
Signs/symptoms of HBV
Acute
- Subclinical: Asymptomatic
- Anicteric - Malaise, anorexia, fever, nausea, vomiting, RUQ pain, rash, vomit
- Icteric - Same with athralgia, jaundice, urticaria
Chronic - May mimic acute
- Cirrhosis: hepatosplenomegaly, portal HTN
- Decompensated cirrhosis - ascites, encephalopathy, coagulopathy, GI bleed
Serology of HBV
Acute infection
Chronic infection
Carrier
Cleared
Vaccinated
High/low viral load
Acute - HBsAg and IgM HBcAb
Chronic - HBsAg and IgG HBcAb
Carrier - HBsAg +/- and IgG HBcAb
Cleared - HBsAb and IgG HBcAb
Vaccinated - HBsAb (vaccination doesnt protect against HBcAb)
High/low viral load - Increased/low HBe
Management of HBV
Acute - supportive; self limiting. Manage complications. HBV Ig
Chronic - Avoid alcohol. Manage cirrhosis, transplant may be needed.
- Antiviral: Nucleotide analogues
- PEGylated interferon (has side effects of haemolytic anaemia, anxiety)
HBV vaccination in 6 in 1 for babies.
Complications of HBV
Fulminant liver failure
Cirrhosis
Decompensated cirrhosis/liver disease
HCC
Define hepatitis C
HCV is an RNA virus of the Flavivirus family. Infection may be acute or chronic and is spread through blood to blood transmission.
Properties of HCV
RNA flavivirus.
2 main types
1a and 1b
Mutate rapidly so difficult to make a vaccine, and previous infection does not confer immunity.
Investigations of HCV
Serology
- HCV antibody
- HCV RNA PCR (GOLD) suggests active infection
Management of HCV
Stop alcohol.
Only treat if viral load not falling
- Triple therapy with NS5A (initiates viral replication) and NS5B (needed for viral replication) inhibitors.
NS5A - End in ASVIR (ledipasvir)
NS5B - End in BUVIR (sofosbuvir)
HDV definition
Enveloped RNA virus with HBV surface antigen on outer envelope; Can only infect where HBsAg already positive.
Co infection - when both acquired together. Indistinguishable from B alone
Super infection - when D acquired in patient with current B infection. Usually more severe and 90% of cases go chronic.
Pathophysiology of HDV
Acute
Coinfection - Similar to B usually full recovery
Superinfection - More severe hepatitis that can go fulminant. May present as exacerbated HBV or new in unknown HBsAg carrier
Chronic
Hep D suppresses Hep B so most damage from Hep D. Severe risk of fulminant failure, cirrhosis and HCC.
Investigations for HDV
- Anti-HDV antibodies (should be tested for if HBsAg is positive)
- HDV RNA PCR GOLD
Management of HDV
Antiviral therapy
Transplant if severe
Hepatitis E definition with epidemiology
Small non enveloped RNA virus causing mainly acute hepatitis but can also lead to chronic in immunosuppressed patients. Has a faecooral spread. Is part of Hepeviridae family
Most common cause of acute hepatitis. Very dangerous in pregnancy (liver failure)
Investigations and management of Hep E
Anti-HEV antibodies
- IgM Active
- IgG Past (No vaccine)
HEV RNA PCR GOLD
- Mostly supportive, self limiting.
Ribaviron if chronic
Define autoimmune hepatitis
Chronic inflammatory condition of liver, characterised by high serum globulin (IgG), inflammatory changes to liver, favourable response to immunosuppression, and presence of circulating antibodies (ANA, Anti-SMA, Anti-SLA/LP, anti-LKM1, anti LC1)
Risk factors for autoimmune hepatitis
Females
Other autoimmune disease
HLA-DR3/4
Viral hepatitis
Genes involved in autoimmune hepatitis
HLA-DR3/DR4
Antibodies in autoimmune hepatitis
Type 1 - Middle-aged women (ANA, ASMA, Anti SLA/LP)
Anti Nuclear Antibody
Anti Smooth Muscle Antibodies
Anti-soluble liver antigen/Liver-pancreas
Type 2 - Young children and early adulthood
Anti-LKM1 (liver kidney microsome 1)
Anti-LC1 (liver cytosol 1)
Signs/symptoms of autoimmune hepatitis
Rash, anorexia, abdominal pain + chronic liver disease symptoms
- Jaundice
- Spider angioma
- Gynaecomastia
- Splenomegaly
- Variceal bleeding
- Encephalopathy
Fatigue, fever, malaise, urtcarial rash, weight loss, amenorrhoea
Investigations in autoimmune hepatitis
- Serum antibodies - present
- Serum globulin - HIGH
- High ALT/AST
- Liver biopsy GOLD: Mononuclear infiltrates
Management of autoimmune hepatitis
Immunosuppression
- Prednisolone + Azathioprine
Liver transplant if REALLY REALLY bad
What are the types of biliary tract disease and what are they usually caused by?
Cholelithiasis - Development of gallstones
- Biliary colic - Acute, severe, self-limiting RUQ pain, caused by gallstones irritating bile ducts. (Stones fall back into gall bladder) RUQ pain
- Cholecystitis - Inflammation of gall bladder, usually due to impacted gallstones (calculous) but can be acalculous. RUQ pain, fever
- Ascending cholangitis - Infection of the biliary tree characteristically resulting in pain fevers and jaundice. RUQ pain, fever, jaundice
- Gallstones can also cause Pancreatitis
Risk factors for gallstone development
6Fs
Female
Fat (BMI>30)
Fertile (pregnant or oestrogen therapy)
Forties+
Fair (white)
Family history
- Haemolytic conditions
- Family history
- Rapid weight loss/ prolonged fasting
- High triglyceride/ cholesterol diet
- Diabetes
Factors leading to gallstone development
- Biliary stasis - Bile flow slows when fasting, high oestrogen, oral contraceptive pill
- Increased cholesterol - Obesity, diabetes
- Decreased bile acids - Cirrhosis, crohn’s, ileal resection
Gallstone composition
- Cholesterol (80%)
- Black pigment (calcium bilirubinate) - Patients with haemolysis
- Brown pigment (calcium salts with bilirubin). Infection association
Complications of gallstone development
Biliary colic
Acute cholecystitis
Acute (ascending) cholangitis
Acute pancreatitis
Obstructive jaundice
Definition, signs/symptoms, and examination of biliary colic
- Pain in RUQ/Epigastrum caused by gallstones irritating bile ducts. Episodes normally last 30 mins-6 hours
- Pain can radiate to right shoulder or around to back. Accompanied by nausea/vomiting
- Examination is normal.
Investigations in biliary colic
Mostly normal. High bilirubin may suggest obstruction of bile ducts and amylase should be checked to exclude pancreatitis
- 1st: Abdominal ultrasound. Will show stones, thin GB wall, dilated cystic ducts (NORMAL bile ducts)
- GOLD: ERCP (endoscopic retrograde cholangiopancreatography) or MRCP (magnetic resonance cholangiopancreatography)
Management of biliary colic
Analgesia (paracetamol or NSAID)
Low fat diet
ERCP allows for retrieval of stones, or cholecystectomy
Gallstone pain radiates to shoulder. What nerve causes this?
Phrenic nerve
Pathophysiology of cholecystitis
Inflammation of the gallbladder usually due to gallstones causing bile stasis.
- Bile stasis irritates gallbladder wall causing mucosa to secrete mucus and inflammatory enzymes.
- Bacteria can grow, (e.g. enterococci, e. coli, clostridium) and go through wall causing peritonitis.
- If stone travels further down, it can cause obstruction of common bile duct causing bile to back up into liver, causing conjugated bilirubin to build up in blood (Jaundice!)
Severe systemic upset, surgery or trauma (sepsis, burn, cancer) can cause acalculous cholecystitis. Fasting and TPN (Total parenteral nutrition - basically IV) can also cause this!
Signs/symptoms of cholecystitis
- Epigastric pain/RUQ radiating to right shoulder/scapula and round to back
- Fever
- Malaise
- Murphy’s sign positive! (palpate GB and ask patient to exhale then inhale, pain on inhalation)
- Jaundice only present if stone travels to common bile duct, or if ascending cholangitis
What is Murphys sign (in detail)
Tests for gallbladder inflammation!
- Hand is placed over RUQ and pressure applied
- Patient should exhale then take deep breath in
- On inhalation, gallbladder moves inferiorly and comes into contact with hand
- If inflamed, this will cause pain and patient will likely stop inhaling.
- This should be negative on left side
Investigations in cholecystitis
FBC - Neutrophils, CRP/ESR high
Serum amylase/lipase (Check pancreatitis) - normal
1st and GOLD - Abdominal ultrasound - stones in gallbladder, thickened gallbladder walls, distended gallbladder
2nd GOLD: MRCP, especially if suspecting CBD stone, or if LFTs are abnormal (ERCP can be used to extract
Management of cholecystitis
NBM, IV fluids
IV Antibiotics (Coamoxiclav)
Urgent Laparoscopic cholecystectomy within 1 week of diagnosis
Percutaneous cholecystostomy if inappropriate (gangrene, sepsis, perforation)
What kind of food aggravates an inflamed gallbladder
Fatty foods
Fat stimulates cholecystokinin which contracts gallbladder
Define ascending (AKA Acute) cholangitis
Infection of biliary tree resulting in RUQ pain, jaundice and fever (charcot’s triad).
Infection secondary to biliary obstruction, promoting growth of usually gram negative bacteria. E. Coli most common
Causes of ascending cholangitis
- Gallstones causing blockage of bile ducts (choledocholithiasis)
- Biliary strictures (narrowing), malignant or benign
- Surgical injury of bile ducts
Non cancer causes of biliary tract strictures
Chronic pancreatitis
ERCP
Blood clots
Radiotherapy/chemotherapy
Signs/symptoms of Ascending Cholangitis
Charcot’s triad
RUQ Pain, fever, jaundice
- Pruritus
- Pyrexia
- Scleral icterus
- Tenderness/distension
What can Charcot’s triad progress to?
Reynolds pentad suggests biliary sepsis/Obstructive ascending cholangitis
Charcots triad (RUQ pain, fever, jaundice) + Hypotension + confusion)
Investigations of ascending cholangitis
FBC - Leukocytosis with neutrophilia
LFT - Obstructive jaundice with raised ALP>ALT (suggesting cholestasis) and bilirubin
Abdominal ultrasound - Common bile duct dilation and gallstones
First line imaging: Abdominal ultrasound
GOLD: MRCP (Magnetic resonance cholangiopancreatography)
Management of ascending cholangitis
Sepsis 6 protocol if severe/Reynolds pentad
IV fluids and analgesia
IV antibiotics if needed (broad spectrum - Metronidazole, cefotaxime)
GOLD: Remove obstruction:
- ERCP (Endoscopic Retrograde Cholangiopancreatography)
- Shockwave lithotripsy (use sound to break stones)
- Stenting of stricture
What is sepsis 6
Give 3 take 3
Administer oxygen
Give IV fluids
Give IV antibiotics (ceftriaxone)
Take blood culture
Check serum lactates
Measure urine output
Red flags for sepsis 6
Confusion
Unresponsive
Hypotension
Tachycardia
High respiratory rate
Hypoxic
Not passing urine
High lactate
Recent chemotherapy
Define Peritonitis with causes
Inflammation of peritonitis
Primary - Spontaneous Bacterial Peritonitis (Ecoli, Klebsiella (G-) or Staph aureus), or ascites
Secondary - Caused by other chemicals such as bile, intestinal perforation, ruptured appendix/ectopic pregnancy
Infection can spread directly or through blood
Signs and symptoms of peritonitis
- Sudden onset severe abdominal pain followed by general collapse and shock.
- Pain begins poorly localised (visceral peritoneum) and becomes better localised (parietal peritoneum)
- Tenderness and guarding of abdomen
- Pain relieved by resting hands on abdomen (preventing movement of peritoneum)
- Patients like to be still
- Ascites
Investigations in SBP
- Ascitic tap - High WCC (neutrophilia)
- Fluid/blood culture
Exclude others
CXR - air under diaphragm = Intestinal obstruction
Amylase/lipase - Pancreatitis
HCG (human chorionic gonadotrophin) - Check pregnancy as cause of pain
Management of SBP
ABC
IV fluids
NG tube insertion
Broad spectrum antibiotic (Cephalosporin)
Surgery
- Laparotomy - Peritoneal lavage (full clean of peritoneal cavity)
Complications of SBP
- Toxaemia/septicaemia
- Local abscess formation
- Kidney failure
- Paralytic ileus
How does increased portal pressure cause varices
Portal vein carries blood from digestive tract, spleen and pancreas to liver.
Portal HTN causes splanchnic vasodilation, decreasing the overall BP. This causes increased cardiac output and salt and water retention as compensatory mechanisms. This causes hyperdynamic circulation and increased portal flow. Increased resistance from liver and increased flow causes blood to shunt into small gastroesophageal veins.
Urine bilirubin and urobilinogen in haemolysis, hepatic disease and biliary obstruction
Haemolysis - B low, U high
Hepatic disease - B high, U negative/decreased
Biliary obstruction - B high, U high
Treatment of oesophageal varices
Prevent bleeding
- Non selective Beta blocker (carvedilol or nadolol)
- Endoscopic variceal band litigation (repeated every 4 weeks till under control, monitored every year)
Active bleeding
- IV Terlipressin to stop bleeding. Broad spectrum antibiotics and blood transfusions to make patient stable if needed
- Urgent endoscopy when stable with Variceal banding
- TIPS (Transjugular Intrahepatic Portosystemic Shunt) if ineffective or contraindicated
Pre hepatic causes of portal HTN
Blockage of portal vein before liver
E.g. Thrombosis, atherosclerosis, embolism
Intra hepatic causes of portal HTN
Distortion of liver architecture
- Cirrhosis
- Schistosomiasis - flatworms in liver
- Sarcoidosis - Granulomas in liver
Post hepatic causes of portal HTN
Venous blockage after liver, causing blood to back up into system
- Right sided heart failure
- Constrictive pericarditis
- Budd-Chiari syndrome
- IVC obstruction
Where can varices develop due to portal HTN
- Inferior part of oesophagus (oesophageal varices)
- Rectum (superior portion of anal canal)
- Anterior abdominal wall via umbilical vein (Caput medusae)
Signs/symptoms of portal HTN
ABCDE
A - Ascites
B - Bleeding of varicose veins
C - Caput Medusae
D - Diminished liver function
E - Enlarged spleen
Haematemesis (vomiting blood) or malaena
Gold standard investigation in portal HTN
Hepatic Venous Pressure Gradient Measurement (HVPGM)
Define Primary Biliary Cholangitis and Primary Sclerosing Cholangitis
PBC - Autoimmune granulomatous destruction of small intrahepatic biliary ducts leading to subsequent leakage of bile into circulation
PSC - Chronic liver disease of intra or extra hepatic bile ducts characterised by inflammation, fibrosis and destruction.
PBC vs PSC
PBC - Autoimmune, associated with other conditions (Sjogrens, Raynauds, Thyroid, RA, Systemic sclerosis), typical presentation is a woman with extreme itching.
PSC - Often asymptomatic, detected by accident, or symptoms of liver dysfunction. Male with history of IBD (mainly UC)
Risk factors for PBC
Female
Autoimmune conditions
Family History
Past pregnancy
Excessive nail polish/hair dye use
Smoking
Pathophysiology of PBC
Anti-Mitochondrial Antibodies (AMA) attack cells lining intrahepatic bile ducts. Causes leakage of bile into the blood. Damage causes inflammation which leads eventually to cirrhosis. ~50% have another associated autoimmune condition.
Signs/symptoms of PBC
Key presentation is middle aged woman with severe itching!
- Pruritus
- Skin hyperpigmentation
- Clubbing
- Xanthelasma
- Scleral icterus
- Fatigue and weight loss
- Hepatosplenomegaly
- Deficiency of fat soluble vitamins (ADEK)
May have an associated autoimmune condition
Investigations in PBC
LFT
- High ALT, ALP, GGT Conjugated Bilirubin
- Low albumin
Antibodies
- AMA antibodies
Abdominal Ultrasound - Extrahepatic cholestasis
MRCP may be needed
Diagnostic criteria for PBC
- High ALP or GGT
- Presence of AMA
- Liver biopsy showing granulomatous inflammation around intrahepatic bile ducts and cirrhosis
Management of PBC
- Ursodeoxycholic acid (bile acid analogue) which dampens inflammatory response, acts an anti-apoptotic agent, improves cholestasis
- Fat soluble vitamin supplements
Cholestyramine to relieve pruritus
Transplant in end stage liver failure
Complications of PBC
- Malabsorption of fat soluble vitamins due to cholestasis
- Coagulopathy possible
- Hypercholesterolaemia
- Liver Cirrhosis
- HCC
- Metabolic bone disease
Pathophysiology of PSC
An autoimmune trigger causes progressive intra and extrahepatic bile duct damage, causing bile duct inflammation, strictures and sclerosis. Strictures obstruct bile flow into intestines.
Between areas of fibrosis/stricturing, some areas are dilated (no fibrosis) giving “beaded” appearance on ERCP/MRCP
Damage leads to:
- Cholestasis
- Bile/toxin build up in liver
- Bile duct strictures
-> End stage liver failure
Too much fibrosis causes portal HTN -> hepatosplenomegaly
Risk factors for PSC (3)
- Male
- Having IBD (UC especially)
- Genetic predisposition/family history
Signs/symptoms of PSC
Usually detected asymptomatic
- Jaundice
- Pruritus
- Fatigue
- RUQ/epigastric abdominal pain
- Symptoms of bowel disease (bloody stools etc)
Investigations in PSC
LFT - ALP, GGT. Conjugated Bilirubin
Antibodies
- pANCA
- NO AMA (PBC only)
MRCP (Multiple biliary strictures showing a “beaded” appearance) (US first in PBC)
- Urinary urobilinogen lowered
ERCP if biopsy needed
(if unclear)
Management of PSC
Cholestyramine for pruritus
Lifestyle changes
Fat soluble vitamins
Liver transplant at end stage
How is PSC monitored
Annual gallbladder ultrasound and colonoscopy - check for precancerous polyps (increased risk of cholangiocarcinoma)
Complications of PSC
- Ascending Cholangitis
- Biliary strictures
- Gallstones
- Metabolic bone disease (Osteopenia/porosis) (lack of vit D)
- End stage liver disease
- Cholangiocarcinoma
- HCC
- Colorectal carcinoma
What is secondary sclerosing/biliary cholangitis
No autoimmune involvement. Other cause possible such as gallstone, surgical complication, malignancy, trauma
Define pancreatitis
Acute or chronic inflammatory damage to the pancreas. Most common causes are gallstones and alcohol. Recurrent bouts of acute can lead to chronic
Causes of acute pancreatitis
IGETSMASHED
Iatrogenic
Gallstones
Ethanol
Trauma
Scorpion/spider bites
Mumps virus
Autoimmune (SLE, Sjogrens)
Steroids
Hypercalcaemia, lipidaemia
ERCP
Drugs (Azathioprine, thiazide diuretic, oestrogen, sitagliptin)
CYSTIC FIBROSIS!!
General pancreatitis pathophysiology
Sudden inflammation causing leakage of enzymes leading to haemorrhaging of the pancreas by its own digestive enzymes (Autodigestion)
General pancreatitis pathophysiology with normal function
Sudden inflammation and haemorrhaging of the pancreas by its own digestive enzymes (Autodigestion). This causes Liquefactive Haemorrhagic Necrosis of the pancreas, if fibrous tissue surrounds this it can become an abscess. Enzymes leak into blood.
Normally, acinar cells secrete inactive enzymes (zymogens) in zymogen vesicles with protease inhibitors (proteases activate them)
Zymogens released into duodenum via pancreatic duct where they are activated by trypsin (which is activated from trypsinogen in the same granules as zymogens)
How does alcohol cause pancreatitis
Alcohol increases zymogen secretion whilst decreasing fluid and bicarbonate secretion by ductal epithelial cells. Pancreatic juice becomes thick and viscous -> Obstruction of pancreatic duct. Fluids and so zymogens back up and zymogen granules fuse with lysosome granules. Lysosomes active trypsinogen into trypsin, which active the zymogens, auto digesting the pancreas.
How do gallstones cause pancreatitis
Gallstones get lodged in sphincter of Oddi, blocking pancreatic secretion release, building up pressure and forcing mixing of granules. Similar mechanism to alcohol.
Signs and symptoms of acute pancreatitis
Sudden severe epigastric pain which radiates to back “like being stabbed in back”. Worsens with movement
- Nausea
- Tachycardia
- Cullens sign (bruising around umbilicus)
- Grey-Turner’s sign (flank bruising)
(bruising caused by bleeding under skin)
History of gallstones or alcohol
Diagnostic investigations in pancreatitis
- Serum amylase and lipase (3x upper limit)
USS to find gallstones
CT for complications (Necrosis, pseudocysts, abscesses, inflammation)
Modified Glasgow scoring
What is the glasgow scoring criteria for pancreatitis
P - PO2 <8
A - Age>55
N - Neutrophils >15X10^9
C - Calcium <2
R - Renal function (urea>16)
E - Enzymes - High AST/LDH
A - Albumin <32
S - Sugar (glucose high)
3 or more in first 48 hours refer up
Ransons also used for mortality and APACHEII for severity but is non specific
What to keep in mind when testing Amylase/ Lipase
Amylase - Rises and falls faster (within 24-48 hours). Non specific
Lipase - More specific for acute pancreatitis. Levels rise slower but have longer half life
Management of pancreatitis
Admission to hospital.
- NBM
- Fluid resuscitation
- Treat gallstones
- Electrolyte replacement
- Oxygen if low
Complications of pancreatitis
- Pancreatic pseudocyst, abscess, necrotising pancreatitis
- Progression to chronic
- Bleeding
Systemic
- Systemic inflammatory response syndrome
- ARDS (acute respiratory distress syndrome)
- Pancreatic diabetes
- Paralytic ileus
- Hypocalcaemia
- Pleural effusions
Define chronic pancreatitis with pathophysiology.
3+ month history pancreatic deterioration leading to irreversible inflammation, calcification, atrophy and fibrosis.
With repeat episodes, the ducts dilate, damaging pancreatic tissue. Stellate cells lay down fibrotic tissue, causing ductal stenosis, leading to acinar cell atrophy. Alcoholic pancreatitis causes calcium deposition.
Healthy pancreatic tissue replaced with
- Misshapen ducts
- Fibrosis
- Calcium deposits
Signs of chronic pancreatitis
Acute signs +
- Steatorrhoea
- Weight loss
- Pancreatic Diabetes
- Skin nodules
Investigations in Chronic Pancreatitis
- Serum amylase/lipase - May be high or low, acinar cell destruction means they cant be produced
- Transabdominal US first! - Atrophic, calcified or fibrotic pancreas
- CT/MRI - Pancreatic calcifications, ductal dilation, atrophy
- ERCP - GOLD - “Chain of lakes” pancreas
- Histology - GOLD - Inflammation, fibrosis, loss of acini, calcification
- Faecal elastase - low (enzyme produced by pancreas)
Management of chronic pancreatitis
1 - abstain smoking + alcohol
- Analgesia for pain
- Replace digestive enzymes and fat soluble vitamins (ADEK)
- ERCP with stent to fix strictures
- Surgical duct drainage, abscess drainage, remove inflamed tissue
Define Wilson’s disease with epidemiology
Autosomal-recessive disease of copper accumulation and toxicity caused by mutation in ATP7B gene, which codes for part of the biliary excretion pathway of copper.
Usually in ~20 year old male. Family history a risk factor
Pathophysiology of Wilson’s Disease
Dysfunction of ATP mediated hepatocyte copper transport, causing increased copper absorption in SI and less hepatic copper excretion.
Copper accumulates in blood, eyes, basal ganglia, liver and kidneys causing
- Hepatic issues
- Neurological issues
- Psychiatric issues
Signs/symptoms of Wilson’s Disease
- Kayser Fleischer Rings (Copper deposits in eyes)
- Hepatic (Jaundice, liver failure signs etc)
- Neurological (Parkinsonism, dysarthria, dementia)
- Kidney (renal tubular acidosis)
- Blood (Haemolytic anaemia)
- Blue nails, arthritis, grey skin, hypermobile joints.
Investigations in Wilson’s
- Ceruloplasmin REDUCED
- 24 hour urinary copper INCREASED
- Slit lamp exam (KF Rings in eyes)
- Liver biopsy GOLD
- Brain MRI - check for BG and cerebellar degeneration
Gene studies/family screening
Treatment of Wilson’s disease
D-penicillamine (copper chelation)
Avoid dietary copper (shellfish, mushrooms)
Liver transplant last resort
(trientine hydrochloride can be used for copper chelation as second choice)
Define haemochromatosis with epidemiology
Autosomal recessive mutation of HFE gene on chromosome 6, causing dysregulated iron absorption and increased release from macrophages.
European Male, 50ish years. (men present earlier than women as menstruation naturally removes iron)
Other causes of iron overload (secondary haemochromatosis)
High intake of iron
Alcoholism
Frequent blood transfusions
Pathophysiology of haemochromatosis
- Missense mutation on HFE gene on chromosome 6
- HFE protein interacts with transferrin receptor 1, and iron is absorbed way more than binding capacity of transferrin
- Hepcidin also reduced, so less iron absorption homeostasis, facilitating iron overload.
- Iron also creates free radicals through Fenton reaction
- This causes damage to LIVER, skin, pancreas, heart, joints, pituitary gland/ gonads
Signs/symptoms of haemochromatosis
- Bronze skin (hyperpigmentation)
- Arthritic joints
- Testicular atrophy/amenorrhoea
- Liver cirrhosis/HCC
- Congestive heart failure
- Osteoporosis and degenerative joint disease
- T1DM and malabsorption if pancreas affected
Investigations in haemochromatosis
Serum iron - high
Serum ferritin - high
Transferrin saturation - high
Total iron binding capacity - Low
Liver biopsy (GOLD) - Prussian blue (Perls) staining
Secondary investigations in haemochromatosis
HbA1c
Joint X ray
CT abdomen
Liver biopsy
ECG
Family screening
Management of haemochromatosis
Venesection - Drain blood to remove iron until serum ferritin 20-30 and transferrin saturation 50%
Then offer maintenance phlebotomy
Iron chelation - Desferrioxamine
Complications of haemochromatosis
Liver
- Cirrhosis HCC
Endocrine
- DM, Hypogonadism, loss of libido
Cardiac
- Myopathy, Congestive heart failure
MSK
- Pseudogout, osteoporosis
Define alpha 1 antitrypsin deficiency
Autosomal recessive disorder (Serpina-1 gene on chromosome 14) causing liver and pulmonary disease.
A1AT is a serine protease inhibitor. In it’s absence, neutrophil elastase destroys elastin in alveoli, causing early, non smoker COPD symptom onset.
In liver, A1AT proteins are misfolded causing them to get stuck in endoplasmic reticulum of hepatocytes, causing cell death, leading to hepatitis, jaundice, etc.
Pathophysiology of A1 Antitrypsin deficiency
A1AT is a protease inhibitor made in liver that normally acts in lungs to protect alveoli from neutrophil elastase. Chromosome 14, Protease inhibitor (Pi) allele on SERINA-1 gene.
PiMM - normal A1AT levels
PiSS - 50% normal A1AT
PiZZ - 10% normal A1AT
PiZZ genotype increases risk of cirrhosis.
In lungs, neutrophil elastase normally destroy harmful causes of infection and inflammation, but also destroy elastin in alveoli, causing panacinar emphysema.
How do smoking and A1AT affect acini differently?
Smoking - Centriacinar destruction and emphysema, primarily upper lobes affected
A1AT - Panacinar destruction/emphysema, most severe in lower lobes
What is an acinus
Functional lung unit, consisting of a bronchiole and its alveoli
Signs/symptoms of A1 antitrypsin deficiency
Respiratory
- Early onset dyspnoea, productive cough
- Prolonged expiratory phase and wheeze
- Pursed lip breathing
- Barrel chest due to hyperexpanded lungs
Liver
- Only in PiZZ genotype, symptoms of cirrhosis (jaundice, hepatomegaly, ascites, coagulopathy, hepatic encephalopathy, portal HTN)
Young, non smoking history
Investigations of A1AT
- Serum A1AT - Reduced
- FEV1/FVC <0.7 (Obstructive pattern)
- LFT deranged
- Liver biopsy with staining. Periodic acid schiff and diastase used (diastase should destroy A1AT). If A1AT deformed, it will stain +ve but be diastase resistant.
- CT chest - panacinar emphysema
- Genetic testing - PiSS, or PiZZ
Management/complications of A1AT
Respiratory
- Smoking cessation
- COPD treatment (bronchodilators and inhaled corticosteroids)
- IV A1AT
Liver
- Avoid alcohol
Liver transplant in end stage
- Respiratory failure and cirrhosis/HCC
- Cholestasis in children
Hernia classifications
Reducible - Can be manually pushed back
Irreducible - Cant be manually pushed back
Obstructed - e.g. bowel contents not being able to pass due to intestinal hernia obstruction
Strangulated - Ischaemia due to blood supply of sac being cut off EMERGENCY
Incarcerated - Contents of hernial sac stuck due to adhesions
Define inguinal hernia with risk factors
Protrusion of abdominal contents through inguinal canal. Most common type of hernia. Usually due to excessive straining/abdominal pressure.
- Male
- Chronic cough
- Constipation
- Heavy lifting
- Urinary obstruction
- Ascites
- Past abdominal surgery
Types of inguinal hernia
Indirect (80%)
- Hernia protrudes into inguinal canal through deep inguinal ring
- Lateral to inferior epigastric artery so can strangulate
Direct (20%)
- Hernia protrudes into inguinal canal through posterior wall (Hesselbach’s triangle)
- These hernias rarely strangulate and are reducible
Signs/symptoms of inguinal hernia
- Swelling in groin (painful if obstruction/strangulation)
- Swelling bulges/expands with coughing or straining
What are the surgical treatment options for hernias
Herniotomy - Contents reduced and sac removed
Herniorrhaphy - Remove sac and repair damaged wall
Hernioplasty - Sac removal and mesh to reinforce weak wall
Define hiatal hernia
Stomach pushes up into lower chest due to diaphragm weakness
Types of hiatal hernia and main signs
Sliding hiatus hernia - Gastrooesophageal junction slides up into chest. This can cause acid reflux as lower oesophageal sphincter becomes less competent
Paraoesophageal (rolling) hernia - GO junction remains in abdomen but bulge of stomach herniates into chest alongside oesophagus. GORD less common
Small hernias are asymptomatic but large hernias can cause symptoms of GORD and dysphagia
Investigations for Hiatal hernia
Upper GI Endoscopy, CXR
Barium Swallow GOLD
Management of hiatal hernia
Weight loss
GORD treatment
Surgical treatment if risk of strangulation
Define Umbilical hernia
Paediatric hernia of intestines through opening in abdominal muscles near navel. Common, harmless, usually self resolve.
Define epigastric hernia
Hernia in midline between belly button and sternum.
Define incisional hernia
Tissue protrudes through weak surgical scar. Usually due to emergency surgery, wound infection, persistent coughing/heavy lifting post op, and poor healing.
Define femoral hernia
Bowel enters femoral canal (mass in upper medial thigh). Occur more in middle aged females.
Irreducible and strangulation likely!
Sum up Gilbert’s syndrome (red)
Hereditary cause of jaundice. Autosomal recessive. Unconjugated bilirubin.
Mostly harmless
Painless jaundice at young age.
If pain or other symptoms, crigler najjar possible (so phototherapy needed to break down bilirubin)
What is the main cause of liver cancer
Metastasis from other cancers (90%)
e.g. Stomach, lung, colon, breast, uterus, pancreas, leukaemia
What is the most common primary liver cancer
Hepatocellular carcinoma (90%)
Causes and metastases of HCC
HBV and HCV!
Autoimmune hepatitis
Cirrhosis
NAFLD
Anabolic steroids
Alcohol
Alfatoxin
Metastasises to lymph, bones, lungs by haematogenous spread
Investigations in HCC
Serum AFP (alpha fetoprotein) (also high in testicular cancer)
Imaging - Ultrasound (1st)
CT can confirm (hard if small lesion)
Biopsy avoided as may causes seeding along biopsy track
Management, prevention and monitoring of HCC
Resect solitary tumours
Percutaneous tumour ablation
Transplant
Prevention
- HBV vaccination
- Reduce alfatoxin exposure
Monitor AFP and do regular ultrasounds (6 months)
Define cholangiocarcinoma with risk factors
Biliary tree cancer, usually adenocarcinoma
- Parasitic worms
- PSC
- Biliary cysts
- HBV/HCV
- DM
Investigations in liver cancers
CT/Ultrasound - identify lesions
MRI - Check benign or malignant
ERCP
AFP, clotting, FBC, LFT, Bilirubin etc to check liver function
Management and prognosis of cholangiocarcinoma
Surgery (not possible in 70% of patients at presentation, as cancer is slow growing)
Liver transplant
- Prognosis poor 5 yr survival - 30%
Signs of liver cancer
Enlarged, irregular, tender liver
Signs of chronic liver disease with decompensation
Weight loss, chronic fatigue
RUQ pain
Define pancreatic cancer with risk factors
Adenocarcinoma of exocrine pancreas ducts. Typically affects head of pancreas.
Extremely poor prognosis
- Male
- Family history
- Obesity
- Alcohol
- Smoking
- Diabetes
- Chronic pancreatitis
- Multiple Endocrine Neoplasia
Signs/symptoms of pancreatic cancer
- Courvoisier’s sign. Painless obstructive jaundice (pale stool, dark urine) + Palpable gallbladder
- Trousseau sign of malignancy - migratory thrombophlebitis (inflammation of veins)
- Weight loss
- Fatigue
- Epigastric pain radiating to back, relieved by sitting forward
Investigations in pancreatic cancer
CT abdomen, chest, pelvis 1st/GOLD
- CA19-9 non specific but raised, and shows disease progression
- PET CT if CT inconclusive
Management of pancreatic cancer
Localised: Surgical resection
- Whipples resection (pancreaticoduodenectomy)
Non localised
- Chemo/radiotherapy
- ERCP to clear obstruction with stenting to provide relief
Monitoring of pancreatic cancer
CA19-9 - non diagnostic but can monitor progression
What is the main sign of malignancy
Trousseau sign - Episodes of migratory thrombophlebitis (inflammation of veins) in different parts of body
Alcoholism screening
CAGE
Cut down (do they feel they should)
Annoyed (by critiques of their habits)
Guilt (do they feel guilty about their habits)
Eye opener (do they drink first thing)
2+ = significant problems
What triad of symptoms is associated with Budd-Chiari syndrome
- Abdominal Pain
- Ascites
- Hepatomegaly
