Liver Flashcards
what are functions of the liver?
- glucose and fat metabolism
- detoxification and excretion
- protein synthesis: albumin and clotting factors
- defence against infection (reticulo-endothelial system)
what can cause acute liver injury?
- viral (A, B, EBV)
- drug e.g. paracetamol OD
- alcohol
- vascular
- obstruction
- congestion
what can cause chronic liver injury?
- alcohol
- viral (B,C)
- autoimmune
- metabolic (iron, copper)
what is the presentation of acute liver injury?
• malaise, nausea, anorexia • occasionally jaundice (doesn’t occur with everyone) • rare: - confusion (encephalopathy) - bleeding - liver pain - hypoglycaemia
what is the presentation of chronic liver injury?
• ascites (fluid accumulation in the peritoneal cavity)
• oedema, haematemesis (varices), malaise, anorexia, wasting, easy bruising, itching, hepatomegaly, abnormal LFTs
• rare:
- jaundice
- confusion
what are results of serum albumin as an LFT?
- marker of synthetic function and is useful for gauging the severity of chronic liver disease: a falling serum albumin is a bad prognostic sign
- in acute liver disease, initial albumin levels may be normal
what are results of bilirubin as an LFT? when is it important to differentiate between conjugated and unconjugated bilirubin?
- is normally almost all unconjugated
- in liver disease, increased serum bilirubin is usually accompanied by other abnormalities in liver biochemistry
- differentiation between conjugated and unconjugated bilirubin is only necessary in congenital disorders of bilirubin metabolism or to exclude haemolysis
what are results of prothrombin time as an LFT?
- mark of synthetic function
- due to its short half-life it is a sensitive indicator of both acute and chronic liver disease
- vitamin K deficiency can cause a prolonged prothrombin time and commonly occurs in biliary obstruction, as the low concentration of bile salts result in poor absorption of vitamin K
- unlike in liver disease, clotting will be corrected by administering 10mg vitamin K IV for 2-3 days
what can be measured in liver biochemistry?
- aminotransferases (aspartate aminotransferase and alanine aminotransferase)
- alkaline phosphate
- bilirubin
- gamma-glutamyl transpeptidase
- total proteins
what are aminotransferases? how are they affected by liver injury?
- these enzymes are contained in hepatocytes and leak into the blood with liver cell damage
- aspartate aminotransferase (AST):
• also present in heart, muscle, kidney and brain
• high levels are seen in hepatic necrosis, myocardial infarction, muscle injury and congestive cardiac failure - alanine aminotransferase (ALT):
• a cytosolic enzyme, more specific to the liver
• more specific to the liver
• a rise only occurs with liver disease
what are levels of alkaline phosphate like in liver injury?
- present in hepatic cancalicular and sinusoidal membranes, bone, intestine and placenta
- raised in both intrahepatic and extrahepatic cholestatic disease of any cause, due to increased synthesis
- raised levels also occur with hepatic infiltrations (e.g. metastases) and in cirrhosis
- highest serum levels (>1000IU/L) occur with hepatic metastasis and primary biliary cirrhosis
where can old/damaged erythrocytes be broken down? how are they broken down?
- old/damaged erythrocytes are broken down by macrophages in the spleen and bone marrow but also in the Kupffer cells (resident macrophages) of the liver
- when the erythrocyte is ingested it is broken down into haem and globin
how is globin metabolised?
- comes from old/damaged erythrocytes
- globin is broken down into amino acids which can then be used to generate new erythrocytes in the bone marrow
how is haem metabolised?
- comes from old/damaged erythrocytes
- haem is further broken down into biliverdin, Fe2+ (transported to bone marrow to be implemented into new erythrocytes by transporter transferrin) and CO
how is biliverdin metabolised?
- comes from haem
- biliverdin is reduced by biliverdin reductase into unconjugated bilirubin; this is toxic and must be secreted, it is lipid soluble and thus insoluble in blood and must be transported bound to albumin to the liver
what catalyses the conversion of biliverdin to unconjugated bilirubin?
biliverdin reductase
what happens to unconjugated bilirubin?
in the liver it undergoes glucuronidation, the addition of a glucuronic acid in order to make it soluble to be excreted, under the action of UDP Glucuronyl Transferase (in Gilbert’s this enzyme is deficient resulting in raised unconjugated bilirubin) which converts it to conjugated bilirubin
what catalyses the conversion of unconjugated bilirubin to conjugated bilirubin? what type of reaction is this?
- UDP Glucuronyl Transferase (deficient in Gilbert’s)
- glucuronidation reaction; addition of a glucuronic acid to make it soluble for excretion
- occurs in the liver
what happens to conjugated bilirubin?
the conjugated bilirubin travels to the small intestine until it reaches the ileum or the beginning of the large intestine where under the action of intestinal bacteria it is reduced through a hydrolysis reaction (a glucuronic acid group is removed) to form urobilinogen
what catalyses the conversion of conjugated bilirubin to urobilinogen? what type of reaction is this?
- intestinal bacteria
- reduced through a hydrolysis reaction (a glucuronic acid group is removed)
- conjugated bilirubin travels to the small intestine until it reaches the ileum/the beginning of the large intestine
what happens to urobilinogen?
- urobilinogen is lipid soluble, around 10% is reabsorbed into the blood and bound to albumin and transported back to the liver where the urobilinogen is oxidised to urobilin
- the remaining 90% of urobilinogen is oxidised by a different type of intestinal bacteria to form stercobilin
what happens to urobilin? how is it formed?
- urobilinogen is lipid soluble, around 10% is reabsorbed into the blood and bound to albumin and transported back to the liver where the urobilinogen is oxidised to urobilin
- in the liver it is either re-cycled into bile or transported into the kidneys where it is excreted in urine
- responsible for the yellowish colour of urine
what happens to stercobilin? how is it formed?
- the remaining 90% of urobilinogen is oxidised by a different type of intestinal bacteria to form stercobilin
- stercobilin is then excreted into the faeces
- responsible for its brownish colour
what is the definition of jaundice?
yellow discolouration of the skin due to raised serum bilirubin
what are causes of unconjugated (pre-hepatic) jaundice?
- Gilbert’s disease (deficiency in UDP glucuronyl transferase)
- haemolysis
what are causes of hepatic conjugated jaundice?
liver disease - hepatitis: • viral (A,B,C,EBV) • drug • immune • alcohol - ischaemia - neoplasm - congestion (congestive cardiac failure)
what are causes of post-hepatic conjugated jaundice?
bile duct obstruction - gall-stones: • bile duct • Mirizzi syndrome (stone in gallbladder/cystic duct presses on the common bile duct = jaundice) - stricture - blocked stent
what is the clinical presentation of pre-hepatic jaundice?
- urine: normal
- stools: normal
- itching: no
- liver tests: normal
what is the clinical presentation of cholestatic (hepatic or post-hepatic) jaundice?
- urine: dark
- stools: may be pale
- itching: maybe
- liver tests: abnormal
what are useful questions to ask about jaundice?
• dark urine, pale stool, itching? - if yes to any then likely to be cholestatic and not prehepatic • symptoms: - biliary pain? - right upper abdomen that radiates to shoulder - rigors? - abdomen swelling? - weight loss? • past history: - biliary disease/intervention? - malignancy? - heart failure? - blood products? - autoimmune disease? • drug history? • social history: - alcohol? - potential hepatitis contact: irregular sex, IV drug use, exotic travel
what is biliary colic?
- the term used for the pain associated with the temporary obstruction of the cystic or common bile duct by a stone migrating from the gall bladder
- the pain of stone-induced ductular obstruction is of sudden onset, severe but constant and has a crescendo-decrescendo characteristic
what is cholecystitis?
gallbladder inflammation
what are the principal bile acids?
- cholic acid
- chenodeoxycholic acid
- glycocholic acid
- taurocholic acid
- deoxycholic acid
- lithocholic acid
what is contained in bile?
- bile salts
- fatty acids
- cholesterol
- phospholipids
- bilirubin
- proteins
- others
- water
what is the epidemiology of gall stones?
- may be present at any age but are unusual before 30s
- increase in prevalence with age
- more common in females than males
- more common in Scandinavians, South Americans and Native North Americans but less common in Asian and African groups
- most form in the gallbladder
- most are asymptomatic
what are the main causes of gall stones?
• obesity and rapid weight loss: - diet high in animal fat and low in fibre • diabetes mellitus • contraceptive pill • liver cirrhosis
what are the risk factors for gall stones?
- female
- fat
- fertile; more kids = increased risk of gallstones
- smoking
what are the 2 types of gallstone?
cholesterol gallstone and bile pigment stones
what is the pathophysiology of cholesterol gallstones?
- accounts for the majority (80%) of gallstones in the Western world
- large stones that are often solitary
- main causes are being female, age and obesity
- cholesterol stone formation is due to cholesterol crystallisation in bile
- cholesterol is held in solution by the detergent action of bile salts and phospholipids, with which it forms micelles and vesicles
- cholesterol gallstones only form in bile which has an excess of cholesterol
- most of cholesterol is derived from hepatic uptake from diet: hepatic biosynthesis of cholesterol only accounts for 20%
why may bile have an excess of cholesterol?
- relative deficiency in bile salts and phospholipids
- relative excess of cholesterol (supersaturated or lithogenic bile) e.g. in diabetes mellitus or in a high cholesterol diet (also decreases bile salt synthesis)
- NOTE: many people with supersaturated bile may never develop stones - it is the balance between cholesterol crystallising and solubilising factors that determines whether cholesterol will crystallised out of solution
what are other factors determining gallstone formation?
- reduced gallbladder motility and stasis e.g. in pregnancy and diabetes
- crystalline promoting factors in bile e.g. mucus and calcium
what is the pathogenesis of bile pigment stones?
• pathogenesis is completely independent of cholesterol gall stones
- mainly formed of Ca2+
• small stones that are friable and irregular
• main cause is haemolysis
• two main types; black and brown
what are the two main types of bile pigment gallstones?
black and brown
what is the pathogenesis and structure of black pigment gallstones?
- calcium bilirubinate composition and a network of mucin glycoproteins that interlace with salts e.g. calcium bicarbonate
- glass-like cross-sectional surface
- seen a lot in patients with haemolytic anaemias e.g.
spherocytosis, sickle cell and thalassaemia - chronic excess of bilirubin
what is the pathogenesis and structure of brown pigment gallstones?
- composed of calcium salts e.g. calcium bicarbonate, fatty acids and calcium bilirubinate
- muddy hue with an alternating brown and tan layer on cross-section
- almost always found in the presence of bile stasis and/or biliary infection
- common cause of recurrent bile duct stones following
cholecystectomy
what is the clinical presentation of gallstones?
- majority of gallstones are asymptomatic
- once gallstones become symptomatic there is a
strong trend towards recurrent complications - gallstones do not cause dyspepsia, fat intolerance, flatulence or other vague upper abdominal symptoms
- biliary or gallstone colic
- acute cholecystitis; obstruction of gallbladder emptying
what is the most common time for onset of symptoms of biliary or gallstone colic?
most common time for onset of symptoms is mid-evening and usually lasts till the early hours of the morning
where is pain in biliary or gallstone colic often located?
- usually epigastrium pain initially but there may be a right upper quadrant component
- radiation of pain may occur over the right shoulder and right subscapular region
- nausea and vomiting frequently accompany the more severe attacks
what is the pathophysiology of acute cholecystitis?
cholecystitis is inflammation of the gallbladder
obstruction of gallbladder emptying:
• the initial event is the obstruction of gallbladder emptying - gallstones are responsible for 95% of cases
• 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
what are symptoms of acute cholecystitis?
- initially there is continuous epigastric pain
- however, slowly there is progression with severe localised right upper quadrant abdominal pain corresponding to parietal peritoneal involvement (as inflammation begins to irritate parietal peritoneum) in the inflammatory process
- pain is associated with tenderness and muscle guarding or rigidity
- vomiting, fever and local peritonitis
how can you differentiate biliary colic, cholecystitis and cholangitis from eachother?
biliary colic:
- right upper quadrant pain
- no fever/increased WCC
- no jaundice
acute cholecystitis:
- right upper quadrant pain
- fever/increased WCC
- no jaundice
cholangitis:
- right upper quadrant pain
- fever/increased WCC
- jaundice
what are differential diagnoses of gallstones?
- biliary colic: irritable bowel syndrome, carcinoma on right colon, renal colic or pancreatitis
- acute cholecystitis: acute episodes of pancreatitis, peptic ulceration, basal pneumonia or an intrahepatic abscess
how are gallstones diagnosed?
- unlikely to be associated with significant abnormality of laboratory tests
- abdominal ultrasound scan is most useful for diagnosing gall stone disease
how is acute cholecystitis diagnosed?
blood tests:
- raised white cell count (due to inflammation) and CRP (c-reactive protein)
- raised serum bilirubin, alkaline phosphatase and
aminotransferase levels
abdominal ultrasound:
- thick walled, shrunken gallbladder
- pericholecystic fluid
- stones
examination:
- right upper quadrant tenderness
- Murphy’s sign: pain on taking a deep breath when examiner places two fingers on right upper quadrant (where gallbladder is)
what is Murphy’s sign?
pain on taking a deep breath when examiner places two fingers on right upper quadrant (where gallbladder is) - seen in acute cholecystitis
what is treatment of gallstones?
- lapraroscopic cholecystectomy
- stone dissolution
- shock wave lithotripsy
what is the treatment of acute cholecystitis?
- nil by mouth
- IV fluids
- opiate analgesia
- IV antibiotics e.g. cefuroxime or ceftriaxone
- cholecystectomy after a few days to allow symptoms to subside
what are some bacteria associated with cholecystitis?
Klebsiella, Enterococcus and Escheria coli (E.coli)
what are features of stone dissolution as a treatment for gallstones?
- for pure or near-pure cholesterol stones these can be solubilised by increasing bile salt content of bile
- give oral ursodeoxycholic acid
- can also give cholesterol lowering agents such as statins e.g. simvastatin
what are features of shock wave lithotripsy as a treatment for gallstones?
- shock wave directed on to gallbladder stones to turn them into fragments so that they can be passed
- the cystic duct requires patency for the fragments to pass
what is ascending/acute cholangitis?
inflammation of the bile duct system
what are the causes of ascending/acute cholangitis?
- most often occurs secondary to common bile duct obstruction by gallstones (choledocholithiasis)
• benign biliary strictures following biliary surgery
• cancer of head of pancreas resulting bile duct obstruction
• in the Far East and mediterranean biliary parasites can cause blockage and ascending/acute cholangitis
what is the clinical presentation of ascending/acute cholangitis (bile duct inflammation)?
- biliary colic
- fever (with rigors), jaundice (preceded by abdominal pain), right upper quadrant pain
- jaundice is cholestatic thus there is dark urine, pale stools and skin may itch
what is choledocholithiasis?
common bile duct obstruction by gallstones
what are features of stones in the common bile duct and ascending/acute cholangitis (bile duct inflammation) on blood tests?
- elevated neutrophil count
- raised ESR and CRP
- raised serum bilirubin - bile duct obstruction if very high
- raised serum alkaline phospahtase
- aminotransferase levels are elevated; ALTs are higher then ASTs normally
what are features of stones in the common bile duct and ascending/acute cholangitis (bile duct inflammation) on a transabdominal ultrasound?
- initial imaging choice
- dilatation of common bile duct
- may or may not show cause of obstruction
- distal common bile duct stones are easily missed
what is treatment of stones in common bile duct and acute cholangitis?
- IV antibiotics e.g. Cefotaxime and Metronidazole; continued after biliary drainage until symptom resolution
- urgent biliary drainage using Endoscopic Retrograde Cholangio-Pancreatography (ERCP) with sphincterotomy (cutting of biliary sphincter):
• removal of stones using basket or balloon
• crushing of stones (mechanical or laser)
• stent placement - surgery is required for large stones
what are clinical presentations of cholelithiasis?
- biliary pain
- cholecystitis
- maybe (Mirizzi) obstructive jaundice
- no cholangitis
- no pancreatitis
what are clinical presentations of choledocholithiasis?
- biliary pain
- no cholecystitis
- obstructive jaundice
- cholangitis
- pancreatitis
what are complications of gallstones in the gallbladder and cystic duct?
- biliary colic
- acute cholecystitis
- empyema - gallbladder fills with pus
- carcinoma
- Mirizzi’s syndrome - stone in gallbladder presses on bile duct causing jaundice
what is Mirizzi’s syndrome?
stone in gallbladder presses on bile duct, causing jaundice
what are complications of gallstones in bile ducts?
- obstructive jaundice
- cholangitis - inflammation of bile duct
- pancreatitis
what is the definition of acute hepatitis?
hepatitis within 6 months of onset
what is the definition of chronic hepatitis?
any hepatitis lasting for 6 months or longer
what are the symptoms of acute hepatitis?
- general malaise
- myalgia (muscle pain)
- GI upset
- abdominal pain - particularly in right upper quadrant
- with/without cholestatic jaundice (pale stools, dark urine)
- tender hepatomegaly
what are infective causes of acute hepatitis?
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)
what are non-infective causes of acute hepatitis?
- alcohol
- drugs
- toxins/poisoning
- pregnancy
- autoimmune
- hereditary metabolic
what are signs of chronic liver disease?
- finger clubbing
- palmar erythema
- dupuytren’s contracture
- spider naevi
- ascites
- gallstones
- itching
- haematemesis
- jaundice
- kidney failure
- weight loss
- fatigue
- easy bruising
what are complications of chronic hepatitis?
- hepatocellular carcinoma (HCC)
* portal hypertension - varices and bleeding
what are infective causes of chronic hepatitis?
- Hepatitis B (+/- D)
- Hepatitis C
what are non-infective causes of chronic hepatitis?
- alcohol
- drugs
- autoimmune
- hereditary metabolic
what is the structure of the hepatitis A virus?
- RNA virus
- acute hepatitis only
what is the epidemiology of Hepatitis A?
- most common acute viral hepatitis in the world, often in epidemics
- endemic in Africa and South America
- most commonly seen in autumn and affects children and young adults
- arises from the ingestion of contaminated food or water e.g. shellfish
- overcrowding and poor sanitation facilitate spread
- notifiable disease
- spread via the faeco-oral route
what are risk factors for Hepatitis A?
- shellfish
- travellers
- food handlers
what is the pathophysiology of Hepatitis A?
- 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
- usually is self-limiting (3-6 weeks); very rarely causes fulminant hepatitis (rapid liver injury that can quickly cause liver failure)
- 100% immunity after infection
what is the clinical presentation of Hepatitis A?
- viraemia causes patient to feel unwell, with non-specific symptoms that include nausea, fever, malaise
- after 1-2 weeks some patients become jaundiced (rare in children) and symptoms often improve
- as the jaundice deepens, the urine becomes dark and the stools pale due to intrahepatic cholestasis
- then hepatosplenomegaly
- after the jaundice lessens (and in the majority of
cases) the illness is over within 3-6 weeks
what are differential diangoses of Hepatitis A?
- other causes of jaundice
- other types of viral and drug-induced hepatitis
what is seen on liver biochemistry in Hepatitis A?
prodromal stage - between initial symptoms and jaundice:
- serum bilirubin normal
- bilurubinuria and raised urinary urobilinogen
- raised serum AST or ALT
icteric stage - once jaundice has presented:
- serum bilirubin reflects the level of jaundice
what is seen on blood tests in Hepatitis A?
- leucopenia
* raised ESR
what are some viral markers for Hepatitis A?
- Hepatitis A Virus (HAV) antibodies
* anti-HAV IgM means acute infection
what is treatment of Hepatitis A infection?
- prognosis is excellent
- supportive treatment
- avoid alcohol
- monitor liver function to spot fulminant hepatic failure (rare)
- manage close contacts by giving human normal immunoglobulin for Hep A to contacts within 14 days as well as vaccination
how can Hepatitis A infection be prevented?
- good hygiene
- resistant to chlorination
- active immunisation
what is the epidemiology of Hepatitis E virus?
RNA virus
• causes a hepatitis similar to hepatitis A i.e. an acute hepatitis only
• common in Indochina
• commoner in older men
• commoner than Hep A in the UK
• mortality is high in pregnancy
• faeco-oral route of transmission; water or food-borne
• usually spread by contaminated water, rodents, dogs and pigs
• usually self-limiting acute hepatitis:
- can cause fulminant hepatitis
- mortality 1-2% (pregnant women its 10-20%)
• chronic disease in the immunosuppressed
what type of virus is Hepatitis E? what is its serology?
- RNA virus
- serology is similar to Hepatitis A (HEV IgM, IgG)
- use HIV RNA to detect chronic infection
what is the treatment/prevention of Hepatitis E virus?
- vaccine available
- prevention via good sanitation and hygiene
- once you’ve had Hep E then you cannot get infected again - 100% immunity
what type of disease is Hepatitis B?
DNA virus; acute and chronic hepatitis
what is the epidemiology of Hepatitis B virus?
- present worldwide
- blood borne transmission
- horizontal transmission
- endemic in Far East, Africa and Mediterranean
- HBV found in semen and saliva
- can result in chronic hepatitis
what is vertical transmission of Hepatitis B virus?
- needle stick (6-20%)
- tattoos
- sexual
- blood products
- IV drug abusers
- vertical transmission - mother to child in utero or soon after birth
what is horizontal transmission of Hepatitis B virus?
- particularly in children
- through minor abrasions or close contact with other children
- HBV can survive on household articles for prolonged periods of time
what are risk factors for Hepatitis B infection?
- healthcare personnel
- emergency and rescue teams
- CKD/dialysis patients
- travellers
- homosexual men
- IV drug users
what is the pathophysiology of Hepatitis B virus?
- DNA virus
- the complete virus comprises of an inner core or nucleocapsid surrounded by an outer envelope of surface protein (Hepatitis B surface antigen (HBsAg))
- HBsAg is produced in excess by the infected hepatocytes and can exist separately from the serum and body fluid
- after penetration into hepatocyte the virus loses its coat and the virus core is transported to the nucleus without processing
- following infection, which may be subclinical, around
1-10% of patients will not clear the virus and will develop chronic Hep B - around 1-5% will develop chronic infection which can lead to cirrhosis and then decompensated cirrhosis and then liver failure
- both cirrhosis and chronic infection can lead to hepatocellular carcinoma
what is the clinical presentation of Hepatitis B virus?
- similar to Hep A
- in many the infection can be subclinical i.e. little symptoms
- incubation period of 1-6 months
- viraemia causes patient to feel unwell, with non-specific symptoms that include nausea, fever, malaise, anorexia and arthralgia (joint pain)
- there may by rashes e.g. urticaria and polyarthritis affecting small joints
- after 1-2 weeks some patients become jaundiced (rare in children) and symptoms often improve
- as the jaundice deepens, the urine becomes dark and the stools pale due to intrahepatic cholestasis
- then hepatosplenomegaly
what is the serology of HBV?
- HBsAg = Hep B surface antigen
- anti HB core IgM increases, peaks then decreases
- anti HB core IgG increases steadily
- total anti-HB core antibody = IgM and IgG
- HbsAg increases, peaks, then decreases up to 6 months
- after 6 months, anti-HBs increase
how is HBV diagnosed?
- HBsAg is present 1-6 months after exposure
- HBsAg presence for more than 6 months implies carrier status
- anti-HBs - antibodies to hepatitis B
what is the treatment for acute hepatitis B?
- supportive
- avoid alcohol
- monitor liver function
- manage close contacts by giving human normal immunoglobulin for Hep B (HBIG) and vaccination
- monitor HBsAg at 6 months to ensure there is full clearance and no progression
- primary prevention is vaccination
- majority will get spontaneous resolution and will not progress to chronic infection
what is the treatment of chronic hepatitis B infection?
- SC pegylated Interferon-alpha 2A
- nuleos(t)ide analogues
what are features of SC pegylated Interferon-alpha 2A as a treatment for chronic hepatitis B infection? what are its side effects?
- immunomodulatory; stimulates immune response
- weekly subcutaneous injection
- offers best long term treatment but only works in some people
- side effects: flu-like illness, fever, lethargy, autoimmune disease, reduction in white cell count and platelets, anxiety and mental issues
what are features of nucleos(t)ide analogues as a treatment for chronic hepatitis B infection?
- inhibit viral replication
- one tablet a day
- high barrier to resistance
- minimal side effects
- may be required life-long since no immune response stimulated
- examples; oral tenofovir or oral entecavir
- need renal monitoring with tenofovir
what type of virus is hepatitis D virus?
- incomplete RNA virus; acute and chronic hepatitis
* requires HBV for assembly
what is the epidemiology of hepatitis D virus?
- common in Eastern Europe e.g. Romania and North Africa
- blood-borne transmission
what are risk factors for HDV?
- IV drug users
- healthcare personnel
- emergency and rescue teams
- CKD/dialysis patients
- travellers
- homosexual men
what is the pathophysiology of HDV?
- Hepatitis D virus is an incomplete RNA particle enclosed in a shell of Hep B surface antigen (HBsAg)
- virus is unable to replicate on its own but is activated by the presence of HBV
- if acquired simultaneously with HBV (co-infection) this causes increased severity of acute infection
- can either occur as co-infection or superinfection
what is co-infection of HDV?
- infection of HBV and HDV
- clinically indistinguishable from acute icteric HBV infection
- serum IgM anti-HDV in the presence of IgM anti-HBV confirms co-infection
what is superinfection of HDV?
- when person who has chronic HBV (which is usually dormant i.e. HBV DNA is low and HDV RNA is high) gets HDV
- results in secondary acute hepatitis and increased rate of liver fibrosis progression
- increase risk of fulminant hepatitis
- rise in serum AST or ALT may be only indication of super-infection
- since it can result in chronic hepatitis can result in hepatocellular carcinoma
what is the treatment of HDV?
SC pegylated interferon-alpha 2A
what type of virus is HCV?
- RNA flavavirus
- acute and chronic hepatitis
what is the epidemiology of HCV?
- very high incidence in Egypt due to failed public health initiative resulting in Hep C spread
- transmitted by blood and blood products and was common in people with haemophilia treated before screening of blood products was introduced
- very high incidence in IV drug users
- limited sexual transmission
- vertical transmission is rare
what are risk factors for HCV?
- IV drug abuse
- men, HIV, high viral load, alcohol
- receiving blood products before screening
what is the pathophysiology of HCV?
- RNA flavovirus
- 7 genotypes; genotype 1a and 1b account for 70% of cases in USA and 50% in Europe
- rapid mutations so envelope proteins change rapidly so it is hard to develop a vaccine
- can result in chronic hepatitis and thus risk of hepatocellular carcinoma
what is the clinical presentation of HCV?
- most acute infections are asymptomatic
- 10% have mild influenza-like illness with jaundice
and a rise in serum aminotransferases (ALT and
AST) - most patients present years later with evidence of
abnormal transferase values at regular health checks or with chronic liver disease - in chronic HCV can result liver cirrhosis, chronic hepatitis, hepatocellular carcinoma
how is HCV diagnosed?
HCV antibody:
• present within 4-6 weeks
• false negative in immunosuppressed (no antibodies produced) and in acute infection (i.e. before 4 weeks)
HCV RNA:
• indicates current infection
• diagnoses acute infection
what is the treatment of acute HCV infection?
- if viral load is falling then no treatment may be required
* but patient should be observed for several months to confirm true viral clearance
what is the treatment of HCV if the HCV RNA does not decline?
SC pegylated Interferon-alpha 2A/B + oral Ribavirin
• pegylated interferon increases risk of mental health side effects
• ribavirin causes haemolytic anaemia and anxiety
- Interferon based drugs have many mental side effects so direct acting antiviral treatment that is interferon free is better
what are features of triple therapy used to treat HCV?
- triple therapy with direct acting antivirals (DAAs) - all are oral:
• NS5A (initiates viral replication) inhibitors end in -asvir e.g. ledipasvir, ombitasvir, ritonasvir
• NS5B (needed for viral replication) inhibitors end in -buvir e.g. sofosbuvir, dasabuvir
• example regimes: - oral ledipasvir + sofosbuvir + ribavirin
- oral ombitasvir + paritaprevir + ritonavir + dasabuvir (NS5B inhibitor) + oral ribavirin
• these regimes are extremely expensive
how is HCV prevented?
- no vaccine
- previous infection does not confer immunity
- screen blood products
- precaution when handling body fluid
what are some mneumonics for viral hepatitis?
- A is Acquired by mouth from Anus, is Always cleared Acutely and only ever Appears once
- E is Even in England and can be Eaten (found in pigs), if not it is always beaten
- B is Blood-Borne and if not Beaten can be Bad
- B and D is DastarDly
- C is usually Chronic but Can be Cured - at a Cost
what is the definition of cirrhosis?
- not a specific disease; it is an end stage of all progressive chronic liver diseases; which once fully developed is irreversible and may be associated
clinically with symptoms and signs of liver failure and portal hypertension - histologically, there is loss of normal hepatic architecture with bridging fibrosis and nodular regeneration
what are common causes of liver cirrhosis?
- chronic alcohol abuse
- non-alcoholic fatty liver disease
- hepatitis B +/- D
- hepatitis C
what are less common causes of liver cirrhosis?
- primary biliary cirrhosis
- autoimmune hepatitis - presents as high ALT
- hereditary haemochromatosis (iron overload)
- Wilson’s disease
- alpha-Antitrypsin deficiency
- drugs e.g. amiodarone and methotrexate
what is the pathophysiology of liver cirrhosis? what does liver injury lead to?
- 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)
what is the role of stellate cells in liver cirrhosis?
stellate cells release cytokines that attract neutrophils and macrophages to the liver which results in further inflammation and thus necrosis and eventual fibrosis
what is the role of kupffer cells in liver cirrhosis?
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
what is the role of myofibroblasts in liver cirrhosis?
- 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 fibrosed tissue is non-functioning
what are the characteristic features of liver cirrhosis?
regenerating nodules separated by fibrous septa and loss of lobular architecture within the nodules
what is micronodular cirrhosis?
- regenerating nodules are usually <3mm in size with uniform involvement of the liver
- often caused by alcohol or biliary tract disease
what is macronodular cirrhosis?
- 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
what is the clinical presentation of liver cirrhosis?
- leuconychia
- finger clubbing
- palmar erythema
- Dupuytren’s contracture
- spider naevi
- xanthelasma
- loss of body hair
- hepatomegaly
- bruising
- ankle swelling and oedema
- abdominal pain due to ascites
what is used to diagnose liver cirrhosis?
- Child-Pugh classification
- liver biopsy (gold standard)
- LFTs
- liver biochemistry
- serum electrolytes: hyponatraemia indicates severe liver disease
- raised serum creatine
- alpha-fetoprotein is highly suggestive of hepatocellular carcinoma
- imaging
what is the Child-Pugh classification?
- used in diagnosis/assessment of liver cirrhosis
• ascites, encephalopathy, (high) bilirubin, (low) albumin and (long) prothrombin given 1-3 and added up to give a score
• < 7 is best and > 10 is sign of bad prognosis
• risk of variceal bleeding is high if > 8
• can also be used to predict mortality and need for liver transplant
what is the role of liver biopsy in diagnosis of liver cirrhosis?
- gold standard
- confirms diagnosis and type and severity of disease
what is the role of LFTs in diagnosis of liver cirrhosis?
- serum albumin and prothrombin time are best indicators of liver function
- low albumin and long prothrombin time indicate cirrhosis (the longer it is correlates to severity)
what is the role of liver biochemistry in diagnosis of liver cirrhosis?
- may be normal depending on severity
* in most cases there is raised AST and ALT
what is seen on imaging in liver cirrhosis?
ultrasound:
- shows change in size and shape of liver - hepatomegaly (small liver in severe disease)
- may be marginal nodularity of the liver surface and distortion of the arterial vascular architecture
- good for detecting hepatocellular carcinoma
CT:
- hepatosplenomegaly
- hepatocellular carcinoma
MRI:
- detects tumours
endoscopy:
- detection of varices and portal hypertensive gastropathy
what are complications of liver cirrhosis?
• coagulopathy; fall in clotting factors II,VII, IX, X
• encephalopathy - liver flap, confusion/coma
• hypoalbuminaemia resulting in oedema
• portal hypertension:
- ascites
- oesophageal varices
what is treatment of liver cirrhosis?
- good nutrition is vital
- alcohol abstinence
- patients should undergo 6 monthly ultrasound screening for early development of hepatocellular carcinoma
- treatment of the underlying causes may arrest or reverse the cirrhosis
- those at risk should have Hep A and B vaccination
- avoid NSAIDs and aspirin as these may precipitate gastro-intestinal bleeding or renal impairment
- reduced salt intake
- if very advanced and no longer responsive to therapy then liver transplantation
what are the main causes of portal hypertension in liver cirrhosis?
pre-hepatic:
- portal vein thrombosis
intra-hepatic:
- cirrhosis (80% UK)
- schistosomiasis (commonest worldwide)
- sarcoidosis
post-hepatic:
- right heart failure (rare)
- constrictive pericarditis
- IVC obstruction
what is the pathophysiology of portal hypertension in liver cirrhosis?
- following liver injury and fibrogenesis, the contraction
of activated myofibroblasts (mediated by endothelin, nitric oxide and prostaglandins) 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 - microvasculature of the gut becomes congested and gives rise to portal hypertensive gastropathies and colopathies
what are sites of collaterals/varices in portal hypertension?
- gastro-oesophageal junction - superficial and tend to rupture
- rectum (30%)
- left renal vein
- diaphragm
- retroperitoneum
what is the clinical presentation of portal hypertension in liver cirrhosis?
- patients are often asymptomatic
- only clinical sign being splenomegaly which is unspecific
- chronic liver disease features present
what are features of variceal haemorrhage? when can it occur?
complication of liver cirrhosis; varices are dilated submucosal veins
• 90% of patients with cirrhosis develop gastro-oesophageal varices over 10 years, but only one-third of these will bleed
• bleeding is likely to occur with large varices or those with red signs at endoscopy and in severe liver disease
what is the initial management of variceal haemorrhage?
- resuscitate until haemodynamically stable
- if anaemic then blood transfusion aiming to get Hb to 80g/L
- correct clotting abnormalities - administer vit K and platelet transfusion
- vasopressin - IV terlipressin to cause vasoconstriction, use IV somatostatin if terlipressin is contraindicated
- prophylactic antibiotics to treat and prevent infection as well as reduce early rebleeding and mortality
- variceal banding; where a band is put around varice using an endoscope, after a few days the banded varice degenerates and falls off leaving a scar
- balloon tamponade to reduce bleeding by placing pressure on varice if banding fails
- transjugular intrahepatic portoclaval shunt (TIPS) - only used when bleeding cannot be controlled wither acutely or following a rebleed, essentially a shunt between the systemic and portal systems which reduces sinusoidal and portal vein pressure
how is variceal haemorrhage prevented?
- non-selective beta-blockade to reduce resting pulse rate to decrease portal pressure
- variceal banding repeatedly to obliterate varices
- liver transplant
what is primary biliary cirrhosis?
- a chronic disorder with progressive destruction of small bile ducts, leading to cirrhosis
- complication of liver cirrhosis
what is the clinical presentation of primary biliary cirrhosis?
- a chronic disorder with progressive destruction of small bile ducts, leading to cirrhosis
- women aged 40-50 yrs constitute 90% patients
- much more common in females than males
- typical age at presentation is 50 yrs
- cause is unknown but its thought to be immunological and serum anti-mitochondrial antibodies (AMA) are found in almost all patients
what are the risk factors for primary biliary cirrhosis?
- positive family history
- many UTIs
- smoking
- past pregnancy
- other autoimmune disease
- use of nail polish/hair dye
what is the pathophysiology of primary biliary cirrhosis?
- interlobar bile ducts are damaged by chronic autoimmune granulomatous inflammation resulting in cholestasis which may lead to fibrosis, cirrhosis and portal hypertension
- serum anti-mitochondrial antibodies (AMA) found in almost all patients
- likely that an environmental factor acts on genetically predisposed hosts to trigger disease
what is the clinical presentation of primary biliary cirrhosis?
- asymptomatic patients are discovered on routine examination or screening and may have hepatomegaly, a raised serum alkaline phosphate or anti-mitochondrial antibodies (AMA)
- pruritus is often the earliest symptom
- lethargy and fatigue may accompany pruritus and precedes jaundice
- when jaundice appears hepatomegaly is usually present
- pigmented xanthelasma on eyelids and deposits of cholesterol in the creases of the hands may be seen
what are complications of primary biliary cirrhosis?
- cirrhosis
- osteoporosis
- malabsorption of fat soluble vitamins (A,D,E,K) due to cholestasis
- decreased bilirubin in the gut lumen results in osteomalacia and coagulopathy
what are differential diagnoses of primary biliary cirrhosis/cholangitis?
- autoimmune cholangitis
- extrahepatic biliary obstruction should be exclude by ultrasound
how can primary biliary cirrhosis be diagnosed by the blood?
- increased alkaline phosphate
- raised serum cholesterol
- anti-mitochondrial antibodies (AMAs); present in 95%, M2 antibody is 98% specific
- raised serum IgM
how can primary biliary cirrhosis/cholangitis be diagnosed with a liver biopsy?
- portal tract infiltrate, mainly of lymphocytes and plasma cells
- around 40% have granulomas
- damage to and loss of small bile ducts and ductular proliferation
- portal tract fibrosis and eventually cirrhosis is seen
what is the treatment of primary biliary cirrhosis/cholangitis?
- ursodeoxycholic acid: improves bilirubin and aminotransferase levels
- supplementation of vitamin A,D,E,K (fat-soluble vitamins)
- bisphosphonates for osteoporosis
- pruritus:
• colestyramine works but unpalatable
• naloxone and naltrexone (opioid antagonists) shown to help - due to lack of effective medical therapy, primary biliary cirrhosis is a major indication for liver transplantation
what is the pathophysiology of alcoholic liver disease? how is alcohol metabolised in the liver?
- ethanol is metabolised in the liver by two pathways, resulting in the increase in the NADH/NAD ratio
- the altered redox potential causes increased hepatic fatty acid synthesis with decreased fatty acid oxidation - this results in the hepatic accumulation of fatty acids which are then esterified to glycerides
- the changes in oxidation-reduction also impair carbohydrate and protein metabolism and are the cause of the centrilobular necrosis of the heaptic
acinus that is typical of alcohol damage - tumour necrosis alpha released from kupffer cells causes the release of reactive oxygen species (ROS), leading to tissue injury and fibrosis
- acetaldehyde is formed by the oxidation of ethanol, and its effect on hepatic proteins could be a factor in producing liver cell damage
- alcohol can enhance the effects of the toxic metabolites of drugs on the liver
what are the main causes of alcoholic liver disease?
- alcohol abuse
- genetic predisposition
- immunological mechanisms
what is the pathophysiology of fatty liver in alcoholic liver disease?
- metabolism of alcohol produces fat in the liver
- this is minimal with small amounts of alcohol, but with larger amounts the cells become swollen with fat (steatosis)
- there is no liver cell damage
- the fat disappears on stopping alcohol
- in some cases, collagen is laid down around the central hepatic veins and this can sometimes progress to cirrhosis without a preceding hepatitis
- alcohol directly affects stellate cells, transforming them into collagen-producing myofibroblast cells
what is the pathophysiology of alcoholic hepatitis in alcoholic liver disease?
- in addition to fatty change there is infiltration by polymorphonuclear leucocytes and hepatocyte necrosis
- dense cytoplasmic inclusions called mallory bodies are sometimes seen in hepatocytes and giant mitochondria are also a feature
- if alcohol consumption continues, alcoholic hepatitis can progress to cirrhosis
what is the pathophysiology of alcoholic cirrhosis in alcoholic liver disease?
classically of the micronodular type but mixed pattern is also seen accompanying fatty change, and evidence of pre-existing alcoholic hepatitis may be present
what is the clinical presentation of fatty liver in alcoholic liver disease?
- 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
what is the clinical presentation of alcoholic hepatitis in alcoholic fatty liver disease?
• 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, occasionally with mild jaundice, may occur, signs of chronic liver disease (ascites, bruising, clubbing, dupuytren’s contracture). liver biochemistry is deranged and the diagnosis is made on liver histology
• in the severe cases the patient is ill, with jaundice and ascites. 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
what is the clinical presentation of alcoholic cirrhosis in alcoholic liver disease?
- represents the final stage of liver disease from alcohol use
- 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
- diagnosis is confirmed by liver biopsy
- there are features of alcohol dependency
how is fatty liver diagnosed?
- elevated MCV indicates heavy drinking
- raised ALT and AST
- ultrasound or CT will demonstrate fatty infiltration as will liver histology
how is alcoholic hepatitis diagnosed?
• leucocytosis • elevated: - serum bilirubin - serum AST and ALT - serum alkaline phosphate
what is the treatment of alcoholic liver disease?
- stop drinking alcohol
• treat delirium tremens with 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 - diet high in vitamins and proteins
what is treatment of fatty liver in alcoholic liver disease?
if patient stops alcohol then fat will disappear and things will go back to normal
what is treatment of alcoholic hepatitis?
- nutrition must be maintained with enteral feeding and if necessary vitamin supplementation
- steroids show short-term benefit
- infections should be treated and/or prevented; anti-fungal prophylaxis should be used
- stop drinking alcohol for life
what is treatment of alcoholic cirrhosis?
- reduce salt intake
- stop drinking for life
- avoid aspirin and NSAIDs
- liver transplantation
how are drugs metabolised in the liver?
drugs are converted from fat-soluble to water-soluble substances that can be excreted in the urine or bile
what are some mechanisms that cause liver damage by drugs?
- disruption of intracellular Ca2+ homeostasis
- disruption of bile canalicular transport mechanisms
- induction of apoptosis
- inhibition of mitochondrial function, which prevents fatty acid metabolism and accumulation of both lactate and reactive oxygen species
how is time course of hepatotoxicity critical?
- most drug reactions occur within 3 months of starting drug
- not so much what drug but what did you start recently?
- onset usually seen 1-12 weeks of starting (earlier is unusual)
- damage may occur several weeks after stopping drug
how should drug hepatotoxicity be approached?
- monitoring liver biochemistry in patients on long-term treatment, such as anti-tuberculosis therapy is essential
- if a drug is suspected of causing hepatic damage it should be stopped immediately
what are the main causes of drug hepatotoxicity?
- antibiotics (30-40%): augmentin, flucloxacillin, TB drugs and erythromycin
- CNS drugs (15%): chlorpromazine, carbamazepine
- immunosuppressants (5%)
- analgesics (20%): diclofenac
- GI drugs (10%) e.g. PPIs
what are drugs that do not cause hepatotoxicity injury?
- low-dose aspirin
- NSAIDs except diclofenac
- beta blockers
- ACE inhibitors
- thiazides
- calcium channel blockers
how is paracetamol metabolised when a therapeutic dose is given?
- predominantly metabolised via a Phase II reaction; conjugated with glucuronic acid and sulphate
- if stores of glucuronic acid and sulphate are running low, then paracetamol will undergo Phase I metabolism via oxidation to produce a highly reactive toxic compound called NAPQI that is then immediately
conjugated with glutathione and subsequently excreted
how is paracetamol metabolised in overdose?
- large amounts of paracetamol are metabolised by oxidation because of saturation of the sulphate conjugation pathway (Phase II reaction)
- liver glutathione stores become depleted so that the liver is unable to conjugate and deactivate the highly reactive, toxic compound NAPQI
- this results in hepatotoxicity and paracetamol-induced kidney injury
what are clinical features of paracetamol (acetaminophen) poisoning?
- following ingestion of an overdose (12g in adults can be fatal) patients usually remain asymptomatic for the first 24 hours and at most develop anorexia, nausea and vomiting with/without right upper quadrant pain
- liver damage is not usually detectable on liver biochemistry until at least 18 hours after ingestion
- liver damage reaches its peak with raised ALT and prothrombin time at 72-96 hours after ingestion
- then will get jaundice and encephalopathy due to liver damage
- with no treatment some patients will develop fulminant hepatic failure
- acute kidney injury due to acute tubular necrosis occurs in 25% of patients who have severe hepatic damage
- metabolic acidosis
- hypoglycaemia (since overdose will inhibit gluconeogenesis)
- prolonged prothrombin time
- raised creatinine
what is the treatment of paracetamol (acetaminophan) poisoning? what are some side effects?
- gastric decontamination: activated charcoal
- give IV N-acetylcysteine which acts by replenishing cellular glutathione stores
• rash is common side effect; treat with chlorphenamine
• do not stop unless anaphylactoid reaction with shock, vomiting and wheeze
how is salicylate (aspirin) metabolised with therapeutic doses?
- aspirin is metabolised to salicylic acid by esterases present in many tissues, especially the liver
- salicylic acid is then further metabolised to salicyluric acid and salicyl phenolic glucuronide
how is salicylate (aspirin) metabolised in overdose?
- these two pathways become saturated
- meaning that the kidneys compensate by increasing renal excretion of salicylic acid - this pathway is extremely sensitive to changes in urinary pH
what are the effects of salicylates in an overdose?
- salicylates stimulate the respiratory centre, and increases the depth and rate of respiration thereby inducing respiratory alkalosis
- salicylates also interfere with carbohydrate, fat and protein metabolism and disrupt oxidative phosphorylation, producing increased concentrations of lactate, pyruvate and ketone bodies all of which contribute to metabolic acidosis
what are some compensatory mechanisms that occur in salicylate (aspirin) overdose?
compensatory mechanisms including renal excretion of bicarbonate and potassium result in metabolic acidosis
what are clinical features of salicylate (aspirin) overdose?
- patients present initially with respiratory alkalosis due to direct stimulation by salicylic acid of the central respiratory centres and then develop metabolic acidosis to compensate
- hyper- or hypoglycaemia may occur
- unlike paracetamol there are many early features:
• hyperventilation and tachypnoea, resulting in respiratory alkalosis
• sweating, vomiting, dehydration, epigastric pain, tinnitus and deafness - rarely in severe poisoning there may be coma and convulsions
what is the treatment of salicylate (aspirin) poisoning?
- severity of salicylate toxicity is dose-related
- fluid and electrolyte replacement with special attention paid to potassium supplementation
- severe metabolic acidosis requires partial correction with the administration of IV sodium bicarbonate
- mild cases only require fluid and electrolyte replacement only
- severe cases may need urine alkalinization (enhances renal elimination of salicylate)
- haemodialysis is the treatment of choice for severely poisoned patients i.e. those with coma and metabolic acidosis
what is hereditary haemochromatosis?
- inherited disorder of iron metabolism in which there is increased intestinal iron absorption leading to iron deposition in joints, liver, heart, pancreas, pituitary, adrenals and skin
- this leads to eventual fibrosis and functional organ failure
what is the epidemiology of hereditary haemochromatosis?
- most common single gene disorder in caucasians
- more common in males than females since menstrual blood loss is protective
- middle-aged men are more frequently and severely affected than women
what are the main causes of hereditary haemochromatosis?
- HFE gene mutation on chromosome 6, this is an autosomal recessive gene - most common cause
- there are other gene mutations responsible and one is autosomal dominant - not as common
- high intake of iron and chelating agents (e.g. ascorbic acid)
- alcoholics may have iron overload
what are risk factors for hereditary haemochromatosis?
- family history since autosomal recessive disease
- alcoholic
what is the role of the HFE gene mutation in the pathophysiology of hereditary haemochromatosis?
- 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
- hepatic expression of the hepcidin gene is decreased in HFE haemochromatosis thereby facilitating iron overload
what is hepcidin? what is its role in hereditary haemochromatosis?
- hepcidin, a protein synthesise 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
what is the total body iron content usually like in hereditary haemochromatosis? where is it particularly increased?
- excess iron is then gradually taken up by the liver and other tissue over a long period
- the iron itself precipitates fibrosis
- in symptomatic patients, the total body iron content is 20-40g (compared with 3-4g in a normal person)
- the iron content is particularly increased in the liver and pancreas but also in other organs e.g. heart, skin and endocrine glands
- in established cases, the liver shows extensive iron deposition and fibrosis
what is the clinical presentation of hereditary haemochromatosis?
- men affected more than women due to menstrual blood loss and lower dietary intake of iron
- most affected individuals present in their 50s
- early on tiredness and arthralgia
- hypogonadism (i.e. less testosterone and oestrogen) secondary to pituitary dysfunction is the most common endocrine function
- later there is slate-grey skin pigmentation, signs of chronic liver disease (ascites, oedema, bruising), hepatomegaly, cirrhosis, dilated cardiomyopathy
and osteoporosis - cardiac manifestations such as heart failure and arrhythmias are common, especially in younger patients
what is the classic triad in gross iron overload?
- bronze skin pigmentation (due to melanin deposition)
- hepatomegaly
- diabetes mellitus
how is hereditary haemochromocytosis diagnosed?
homozygous e.g. HFE:
• raised serum iron
• raised serum ferritin (but note any inflammatory process can raised
ferritin)
• liver biochemistry is often normal even with established cirrhosis
heterozygotes e.g. other genes:
• may have normal biochemical tests
• slightly raised serum iron transferrin saturation or serum ferritin
- if iron studies are abnormal can do genetic testing to confirm
MRI:
• detects iron overload
liver biopsy:
• can establish extent of tissue damage and disease severity
ECG/ECHO if cardiomyopathy suspected
what is treatment of hereditary haemochromatosis?
- venesection
- treat diabetes
- testosterone replacement
- in patients who cannot tolerate venesection (due to severe cardiac disease or anaemia), chelation therapy with desferrioxamine is effective
- diet low in iron - tea, coffee or red wine will reduce iron absorption
- avoid fruit/fruit juice (high in vitamin C) and white white as these increase iron absorption
- screening
how is venesection used to treat hereditary haemochromatosis?
- regular removal of blood so body can use some of the excess iron to make new RBCs
- prolongs life and may reverse tissue damage
- required lifelong - done 3-4 times a year
- monitor serum iron and ferritin (should remain in normal range) during venesection
what is Wilson’s disease?
- rare inherited disorder of biliary copper excretion with too much copper in the liver and CNS (basal ganglia)
- autosomal recessive disorder of a gene on chromosome 13 resulting in a molecular defect within a copper-transporting ATPase
what is the epidemiology of Wilson’s disease?
- more common in caucasians than in Indians and Asians
- occurs worldwide especially in countries where marrying first degree relatives is common
label
components of biliary tree
- common hepatic duct
- cystic duct
- common bile duct
- pancreatic duct
- hepatopancreatic ampulla of vater
