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My Phase 2a > Liver > Flashcards

Liver Flashcards

1
Q

what are functions of the liver?

A
  • glucose and fat metabolism
  • detoxification and excretion
  • protein synthesis: albumin and clotting factors
  • defence against infection (reticulo-endothelial system)
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2
Q

what can cause acute liver injury?

A
  • viral (A, B, EBV)
  • drug e.g. paracetamol OD
  • alcohol
  • vascular
  • obstruction
  • congestion
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3
Q

what can cause chronic liver injury?

A
  • alcohol
  • viral (B,C)
  • autoimmune
  • metabolic (iron, copper)
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4
Q

what is the presentation of acute liver injury?

A 
• malaise, nausea, anorexia
• occasionally jaundice (doesn’t occur with everyone)
• rare:
- confusion (encephalopathy)
- bleeding
- liver pain
- hypoglycaemia
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5
Q

what is the presentation of chronic liver injury?

A

• ascites (fluid accumulation in the peritoneal cavity)
• oedema, haematemesis (varices), malaise, anorexia, wasting, easy bruising, itching, hepatomegaly, abnormal LFTs
• rare:
- jaundice
- confusion

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6
Q

what are results of serum albumin as an LFT?

A
  • 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
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7
Q

what are results of bilirubin as an LFT? when is it important to differentiate between conjugated and unconjugated bilirubin?

A
  • 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
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8
Q

what are results of prothrombin time as an LFT?

A
  • 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
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9
Q

what can be measured in liver biochemistry?

A
  • aminotransferases (aspartate aminotransferase and alanine aminotransferase)
  • alkaline phosphate
  • bilirubin
  • gamma-glutamyl transpeptidase
  • total proteins
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10
Q

what are aminotransferases? how are they affected by liver injury?

A
  • 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
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11
Q

what are levels of alkaline phosphate like in liver injury?

A
  • 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
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12
Q

where can old/damaged erythrocytes be broken down? how are they broken down?

A
  • 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
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13
Q

how is globin metabolised?

A
  • 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

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14
Q

how is haem metabolised?

A
  • 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
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15
Q

how is biliverdin metabolised?

A
  • 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
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16
Q

what catalyses the conversion of biliverdin to unconjugated bilirubin?

A

biliverdin reductase

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17
Q

what happens to unconjugated bilirubin?

A

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

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18
Q

what catalyses the conversion of unconjugated bilirubin to conjugated bilirubin? what type of reaction is this?

A
  • UDP Glucuronyl Transferase (deficient in Gilbert’s)
  • glucuronidation reaction; addition of a glucuronic acid to make it soluble for excretion
  • occurs in the liver
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19
Q

what happens to conjugated bilirubin?

A

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

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20
Q

what catalyses the conversion of conjugated bilirubin to urobilinogen? what type of reaction is this?

A
  • 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
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21
Q

what happens to urobilinogen?

A
  • 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
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22
Q

what happens to urobilin? how is it formed?

A
  • 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
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23
Q

what happens to stercobilin? how is it formed?

A
  • 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
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24
Q

what is the definition of jaundice?

A

yellow discolouration of the skin due to raised serum bilirubin

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25
what are causes of unconjugated (pre-hepatic) jaundice?
* Gilbert's disease (deficiency in UDP glucuronyl transferase) * haemolysis
26
what are causes of hepatic conjugated jaundice?
``` liver disease - hepatitis: • viral (A,B,C,EBV) • drug • immune • alcohol - ischaemia - neoplasm - congestion (congestive cardiac failure) ```
27
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 ```
28
what is the clinical presentation of pre-hepatic jaundice?
- urine: normal - stools: normal - itching: no - liver tests: normal
29
what is the clinical presentation of cholestatic (hepatic or post-hepatic) jaundice?
- urine: dark - stools: may be pale - itching: maybe - liver tests: abnormal
30
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 ```
31
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
32
what is cholecystitis?
gallbladder inflammation
33
what are the principal bile acids?
- cholic acid - chenodeoxycholic acid - glycocholic acid - taurocholic acid - deoxycholic acid - lithocholic acid
34
what is contained in bile?
- bile salts - fatty acids - cholesterol - phospholipids - bilirubin - proteins - others - water
35
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
36
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 ```
37
what are the risk factors for gall stones?
- female - fat - fertile; more kids = increased risk of gallstones - smoking
38
what are the 2 types of gallstone?
cholesterol gallstone and bile pigment stones
39
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%
40
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
41
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
42
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
43
what are the two main types of bile pigment gallstones?
black and brown
44
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
45
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
46
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
47
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
48
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
49
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
50
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
51
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
52
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
53
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
54
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)
55
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
56
what is treatment of gallstones?
- lapraroscopic cholecystectomy - stone dissolution - shock wave lithotripsy
57
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
58
what are some bacteria associated with cholecystitis?
Klebsiella, Enterococcus and Escheria coli (E.coli)
59
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
60
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
61
what is ascending/acute cholangitis?
inflammation of the bile duct system
62
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
63
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
64
what is choledocholithiasis?
common bile duct obstruction by gallstones
65
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
66
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
67
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
68
what are clinical presentations of cholelithiasis?
- biliary pain - cholecystitis - maybe (Mirizzi) obstructive jaundice - no cholangitis - no pancreatitis
69
what are clinical presentations of choledocholithiasis?
- biliary pain - no cholecystitis - obstructive jaundice - cholangitis - pancreatitis
70
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
71
what is Mirizzi's syndrome?
stone in gallbladder presses on bile duct, causing jaundice
72
what are complications of gallstones in bile ducts?
* obstructive jaundice * cholangitis - inflammation of bile duct * pancreatitis
73
what is the definition of acute hepatitis?
hepatitis within 6 months of onset
74
what is the definition of chronic hepatitis?
any hepatitis lasting for 6 months or longer
75
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
76
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)
77
what are non-infective causes of acute hepatitis?
- alcohol - drugs - toxins/poisoning - pregnancy - autoimmune - hereditary metabolic
78
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
79
what are complications of chronic hepatitis?
* hepatocellular carcinoma (HCC) | * portal hypertension - varices and bleeding
80
what are infective causes of chronic hepatitis?
- Hepatitis B (+/- D) | - Hepatitis C
81
what are non-infective causes of chronic hepatitis?
- alcohol - drugs - autoimmune - hereditary metabolic
82
what is the structure of the hepatitis A virus?
- RNA virus | - acute hepatitis only
83
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
84
what are risk factors for Hepatitis A?
- shellfish - travellers - food handlers
85
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
86
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
87
what are differential diangoses of Hepatitis A?
- other causes of jaundice | - other types of viral and drug-induced hepatitis
88
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
89
what is seen on blood tests in Hepatitis A?
* leucopenia | * raised ESR
90
what are some viral markers for Hepatitis A?
* Hepatitis A Virus (HAV) antibodies | * anti-HAV IgM means acute infection
91
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
92
how can Hepatitis A infection be prevented?
* good hygiene * resistant to chlorination * active immunisation
93
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
94
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
95
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
96
what type of disease is Hepatitis B?
DNA virus; acute and chronic hepatitis
97
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
98
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
99
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
100
what are risk factors for Hepatitis B infection?
- healthcare personnel - emergency and rescue teams - CKD/dialysis patients - travellers - homosexual men - IV drug users
101
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
102
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
103
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
104
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
105
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
106
what is the treatment of chronic hepatitis B infection?
- SC pegylated Interferon-alpha 2A | - nuleos(t)ide analogues
107
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
108
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
109
what type of virus is hepatitis D virus?
* incomplete RNA virus; acute and chronic hepatitis | * requires HBV for assembly
110
what is the epidemiology of hepatitis D virus?
- common in Eastern Europe e.g. Romania and North Africa | - blood-borne transmission
111
what are risk factors for HDV?
- IV drug users - healthcare personnel - emergency and rescue teams - CKD/dialysis patients - travellers - homosexual men
112
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
113
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
114
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
115
what is the treatment of HDV?
SC pegylated interferon-alpha 2A
116
what type of virus is HCV?
- RNA flavavirus | - acute and chronic hepatitis
117
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
118
what are risk factors for HCV?
- IV drug abuse - men, HIV, high viral load, alcohol - receiving blood products before screening
119
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
120
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
121
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
122
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
123
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
124
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
125
how is HCV prevented?
* no vaccine * previous infection does not confer immunity * screen blood products * precaution when handling body fluid
126
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
127
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
128
what are common causes of liver cirrhosis?
- chronic alcohol abuse - non-alcoholic fatty liver disease - hepatitis B +/- D - hepatitis C
129
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
130
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)
131
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
132
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
133
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
134
what are the characteristic features of liver cirrhosis?
regenerating nodules separated by fibrous septa and loss of lobular architecture within the nodules
135
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
136
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
137
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
138
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
139
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
140
what is the role of liver biopsy in diagnosis of liver cirrhosis?
- gold standard | - confirms diagnosis and type and severity of disease
141
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)
142
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
143
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
144
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
145
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
146
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
147
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
148
what are sites of collaterals/varices in portal hypertension?
* gastro-oesophageal junction - superficial and tend to rupture * rectum (30%) * left renal vein * diaphragm * retroperitoneum
149
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
150
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
151
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
152
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
153
what is primary biliary cirrhosis?
- a chronic disorder with progressive destruction of small bile ducts, leading to cirrhosis - complication of liver cirrhosis
154
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
155
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
156
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
157
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
158
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
159
what are differential diagnoses of primary biliary cirrhosis/cholangitis?
- autoimmune cholangitis | - extrahepatic biliary obstruction should be exclude by ultrasound
160
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
161
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
162
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
163
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
164
what are the main causes of alcoholic liver disease?
* alcohol abuse * genetic predisposition * immunological mechanisms
165
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
166
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
167
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
168
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
169
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
170
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
171
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
172
how is alcoholic hepatitis diagnosed?
``` • leucocytosis • elevated: - serum bilirubin - serum AST and ALT - serum alkaline phosphate ```
173
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
174
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
175
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
176
what is treatment of alcoholic cirrhosis?
* reduce salt intake * stop drinking for life * avoid aspirin and NSAIDs * liver transplantation
177
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
178
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
179
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
180
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
181
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
182
what are drugs that do not cause hepatotoxicity injury?
* low-dose aspirin * NSAIDs except diclofenac * beta blockers * ACE inhibitors * thiazides * calcium channel blockers
183
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
184
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
185
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
186
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
187
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
188
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
189
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
190
what are some compensatory mechanisms that occur in salicylate (aspirin) overdose?
compensatory mechanisms including renal excretion of bicarbonate and potassium result in metabolic acidosis
191
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
192
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
193
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
194
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
195
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
196
what are risk factors for hereditary haemochromatosis?
- family history since autosomal recessive disease | - alcoholic
197
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
198
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
199
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
200
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
201
what is the classic triad in gross iron overload?
* bronze skin pigmentation (due to melanin deposition) * hepatomegaly * diabetes mellitus
202
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
203
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
204
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
205
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
206
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
207
what are risk factors for Wilson's disease?
family history
208
how is copper normally absorbed/metabolised?
- dietary copper is normally absorbed from the stomach and upper small intestine - copper is transported to the liver loosely bound to albumin - once in the liver it is incorporated into a glycoprotein called caeruloplasmin (synthesised in the liver) and secreted into the blood - the remaining copper is normally excreted in the bile and excreted in faeces
209
what is the pathophysiology of Wilson's disease?
- Wilson’s disease is a very rare inborn error of copper metabolism that results in copper deposition in various organs, including the liver, the basal ganglia of the brain and the cornea - the precise mechanism for the failure of copper metabolism is unknown - liver histology is not diagnostic but varies from that of chronic hepatitis to macronodular cirrhosis - the basal ganglia are damaged and show cavitation, the kidneys show tubular degeneration and erosions are seen in the bones - it is potentially treatable and all young patients with disease must be screened for this condition
210
what is the clinical presentation of Wilson's disease?
- children usually present with hepatic problems e.g. hepatitis, cirrhosis and fulminant liver failure - young adults tend to present with more CNS problems e.g. tremor, dysarthria (slurred or slowed speech), involuntary movements, dysphagia, dyskinesia (impaired voluntary movement) and eventual dementia - reduced memory - liver disease varies from episodes of acute hepatitis, especially in children (which can progress to acute hepatic failure), to chronic hepatitis to cirrhosis - Kayser-Fleischer ring - caused by copper deposition in cornea, results in a greenish-brown pigment at the corneoscleral junction
211
what is a Kayser-Fleischer ring?
caused by copper deposition in cornea, results in a greenish-brown pigment at the corneoscleral junction
212
how is Wilson's disease diagnosed?
- serum copper and caeruloplasmin are usually reduced but can be normal - 24 hour urinary copper excretion is high - liver biopsy shows increased hepatic copper, hepatitis and cirrhosis - but note high copper levels are also found in chronic cholestasis - haemolysis and anaemia may be present - MRI will show basal ganglia and cerebellar degeneration
213
what is the treatment of Wilson's disease?
- avoid foods that are high in copper e.g. liver, chocolate, nuts, mushrooms and shellfish - lifelong chelating agent e.g. penicillamine used to chelate copper - liver transplant if severe disease - screen siblings as asymptomatic homozygotes need treating
214
what foods should be avoided in Wilson's disease?
avoid foods that are high in copper e.g. liver, chocolate, nuts, mushrooms and shellfish
215
what lifelong chelating agent is used in Wilson's disease? what are some side effects?
lifelong chelating agent e.g. penicillamine used to chelate copper - skin rashes - fall in white cell count, Hb and platelets - haematuria - renal damage
216
what is alpha-1-antitrypsin deficiency? what can it affect?
- an inherited autosomal recessive conformational disease that can be fatal - alpha-1-antitrypsin gene is located on chromosome 14 - alpha-1-antitrypsin’s main function is to inhibit the proteolytic enzyme neutrophil elastase - this deficiency affects the lung (emphysema) and liver (cirrhosis and hepatocellular cancer) and can present in homozygous and heterozygous forms
217
what is the epidemiology of alpha-1-antitrypsin deficiency?
more common in caucasians
218
what are the consequences of alpha-1-antitrypsin deficiency?
* emphysema * liver cirrhosis * hepatocellular carcinoma
219
what is the clinical presentation of alpha-1-antitrypsin deficiency? how does this differ in children vs adults?
- majority of symptomatic patients are homozygotes with a PiZZ phenotype - in children it tends to present as liver disease i.e liver cirrhosis, hepatitis and cholestatic jaundice - in adults it tends to present as respiratory problems (dyspnoea) i.e. emphysema - around 10-15% of adults will develop cirrhosis, usually over the age of 50 - 75% will have respiratory problems - heterozygotes may develop liver disease but risk is small
220
how is alpha-1-antitrypsin deficiency diagnosed?
low serum alpha-1-antitrypsin levels
221
what is treatment of alpha-1-antitrypsin deficiency?
- no treatment - treat complications of liver disease - stop smoking - those with hepatic decompensation should be assessed for liver transplant - manage emphysema
222
what is hepatic failure?
hepatic failure occurs when the liver loses the ability to regenerate or repair, so that decompensation occurs
223
what is acute hepatic failure?
acute live injury with encephalopathy and deranged coagulation (INR > 1.5) in a patient with a previously normal liver
224
what is acute-on-chronic hepatic failure?
liver failure as a result of decompensation of chronic liver disease
225
what is the pathophysiology of hepatic encephalopathy?
- as the liver fails, nitrogenous waste e.g. ammonia builds up in the circulation and passes to the brain which can result in permanent brain damage as ammonia is neurotoxic to the brain since it halts the Krebs cycle resulting in irreparable cell damage and neural cell death - also as astrocytes try to clear ammonia (using a process involving the conversion of glutamate to glutamine), the excess glutamine causes an osmotic imbalance and a shift of fluid into these cells, hence cerebral oedema, resulting in damage
226
what are clinical presentations of hepatic encephalopathy?
- confusion, coma, asterixis and drowsiness - abnormal bleeding - ascites - jaundice
227
what is fulminant hepatic failure?
clinical syndrome resulting from massive necrosis of liver cells leading to severe impairment of liver function
228
how can fulminant hepatic failure be classified?
- hyperacute: encephalopathy within 7 days of jaundice onset - acute: encephalopathy within 8-28 days of jaundice onset - subacute: within 5-26 weeks - there is a decreasing risk of cerebral oedema as the onset of encephalopathy is increasingly delayed
229
what is responsible for most cases of liver failure?
paracetamol overdose (50% of cases)
230
what are histological features of liver failure?
histologically there is multiacinar necrosis involving a substantial part of the liver
231
what are the main causes of liver failure?
* virus * drugs * hepatocellular carcinoma * Wilson’s disease or alpha-1-antitrypsin deficiency * acute fatty liver of pregnancy
232
what are viruses that cause liver failure?
- Hep A,B (and thus D),E but rarely C - cytomegalovirus - EBV - herpes simplex virus
233
what are drugs that cause liver failure?
- paracetamol; common cause - alcohol - anti-depressants; amitriptyline - NSAIDs - ecstasy or cocaine - antibiotics - ciprofloxacin, doxycycline or erythromycin
234
what is the clinical presentation of liver failure?
- jaundiced patient - small liver - signs of hepatic encephalopathy - fetor hepaticus; patient smells like pear drops - cerebral oedema - signs of chronic liver disease suggest acute-on-chronic hepatic failure - fever, vomiting and hypertension - neurological examination shows spasticity and hyper-reflexia; plantar responses remain flexor until late
235
how can hepatic encephalopathy be graded?
I: altered mood/behaviour, sleep disturbance, dyspraxia II: increasing drowsiness, confusion, slurred speech +/- liver flap, inappropriate behaviour/personality change III: incoherent, restless, liver flap, stupor IV: coma
236
what are differential diagnoses of liver failure?
- structural/space occupying lesions in the brain - cerebral infection; bacterial or viral - drug or alcohol intoxication - hypoglycaemia, electrolyte imbalance or hypoxia
237
how is liver failure diagnosed with blood?
* hyperbilirubinaemia * high serum ALT and AST * low levels of coagulation factors and raised prothrombin time * low glucose * ammonia levels high
238
how is liver failure diagnosed with imaging?
* electroencephalogram (EEG) useful in grading encephalopathy * ultrasound will define liver size and may indicate underlying liver pathology * CXR * doppler ultrasound to see hepatic vein patency
239
how is liver failure diagnosed with microbiology?
* blood culture * urine culture * ascitic tap to check for pathogens
240
what is the treatment of liver failure?
- treat cause e.g. for paracetamol poisoning give N-acetyl-cysteine - monitor glucose levels and administer IV glucose if necessary - signs of raised intracranial pressure give IV mannitol - mineral supplements e.g. calcium, potassium, phosphate etc. - coagulopathy is managed with IV vitamin K, platelets, blood or fresh frozen plasma - reduce haemorrhage risk by giving PPI to reduce GI bleeds - prophylaxis against bacterial and fungal infection - liver transplant
241
what is ascites?
ascites is the accumulation of free fluid within the peritoneal cavity
242
what is the epidemiology of ascites?
- 10-20% survival 5-years from onset - signifies other serious illness! - common complication of cirrhosis - common postop - poor prognosis
243
what are the main causes of ascites?
- local inflammation - low protein - low flow
244
how does local inflammation cause ascites? where is it seen in?
- typically with peritonitis or intra-abdominal surgery - local inflammation leads to fluid accumulation - seen in: • peritonitis • abdominal cancers (especially ovarian) • infection e.g. TB
245
how does low protein cause ascites? where is it seen in?
- with less protein e.g. albumin there is an inability to pull fluid back into the intravascular space - this fluid then accumulates in the peritoneum - seen in: • hypoalbuminaemia • nephrotic syndrome • malnutrition
246
how does low flow cause ascites? where is it seen in?
- fluid cannot move forwards through system e.g. due to a clot - raises pressure in vessels causing fluid to leak out of the vessels - seen in: • cirrhosis i.e. portal hypertension • budd-chiari syndrome (occlusion of hepatic veins that drain liver) • cardiac failure • constrictive pericarditis
247
what are risk factors for ascites?
- high sodium diet - hepatocellular carcinoma - splanchnic vein thrombosis resulting in portal hypertension
248
what is the clinical presentation of ascites?
- abdominal swelling may develop over days or several weeks - distended abdomen - fullness in the flanks and shifting dullness - mild abdominal pain and discomfort are common - if severe pain then raises suspicion of bacterial peritonitis - respiratory distress and difficulty eating accompany tense ascites - may be scratch marks on abdomen caused by itching due to jaundice i.e. liver failure - many patients also have peripheral oedema
249
how is ascites diagnosed?
- presence of fluid is confirmed by demonstrating shifting dullness - diagnostic aspiration of 10-20ml of fluid using ascitic tap for - protein measurement of ascitic fluid from ascitic tap:
250
what is looked for in an ascitic tap?
* raised white cell count - indicative of bacterial peritonitis * Gram stain and culture * cytology to find malignancy * amylase to exclude pancreatic ascites
251
what is found in a protein measurement of ascitic fluid from an ascitic tap? what causes this?
transudate (less bad); low protein (< 30g/L) -transparent i.e. no/little protein: - portal hypertension e.g. cirrhosis - constrictive pericarditis - cardiac failure - Budd-Chiari syndrome exudate (extremely bad); high protein (> 30g/L) - exudes protein: - malignancy - peritonitis - pancreatitis - peritoneal tuberculosis - nephrotic syndrome
252
what is treatment of ascites?
- treat underlying cause - reduce sodium to help liver and reduce fluid retention - increase renal sodium excretion - diuretic of choice is an aldosterone antagonist e.g. oral spirolactone since it spares K+ - paracentesis; can drain 5 litres at time, used to relieve symptomatic tense ascites - shunts
253
what is TIPS? how is it used to treat ascites?
Transjugular Intrahepatic Portosytemic Shunt: - used for resistant ascites - can be risky
254
what is peritonitis?
the inflammation of the peritoneum
255
what are the two parts of the peritoneum? what innervates them?
parietal - covers the abdominal wall - somatic innervation - sensation is well localised visceral - on organs e.g. stomach, liver and colon - autonomic innervation - sensation is poorly localised
256
what are the anatomical limits and site of autonomic pain of the foregut?
- lower oesophagus to D2 (liver, spleen and gallbladder) | - epigastric
257
what are the anatomical limits and site of the autonomic pain of the midgut?
- D2 to 2/3 across transverse colon (majority of the abdomen) - periumbilical
258
what are the anatomical limits and site of the autonomic pain of the hindgut?
- transverse colon to upper rectum | - hypogastric
259
what is the peritoneal cavity? what does it contain?
- peritoneal cavity is a closed sac lined by mesothelial cells; these produce surfactant, which acts as a lubricant within the peritoneal cavity - the cavity contains <100mL of serous fluid containing <30g/L of protein (transudate)
260
what allows particulate matter to be removed rapidly from the peritoneal cavity?
- the mesothelial cells lining the diaphragm have gaps that allow communication between the peritoneum and the diaphragmatic lymphatics - around 1/3rd of fluid drains through these lymphatics, the remainder through the parietal peritoneum - these mechanisms allow particulate matter to be removed rapidly from the peritoneal cavity
261
what is primary peritonitis characterised by?
- inflammation on its own: • spontaneous bacterial peritonitis • ascites - diagnosis is an ascitic tap and blood cultures - treatment is with broad spectrum antibiotics
262
what is secondary peritonitis characterised by?
- caused by something else e.g. chemicals | - treat the cause, primarily via surgery
263
what are the main causes of peritonitis?
bacterial and chemical
264
what are some bacterial causes of peritonitis?
- gram negative coliforms e.g E.coli and Klebsiella - gram positive staphylococcus e.g. Staphylococcus aureus; Staphylococci are found on the skin and can get into the peritoneal cavity through tubes placed through skin - mode of action: can result in peritonitis either through irritation of the peritoneum e.g. perforated appendix or spontaneous bacterial peritonitis
265
what are some chemical causes of peritonitis?
- bile - old clotted blood - mode of action: • chemical irritation due to leakage of intestinal contents • ruptured ectopic pregnancy - with blood release, followed by infection
266
what is the clinical presentation of peritonitis?
- perforation = sudden onset: • sudden onset with acute severe abdominal pain followed by general collapse and shock - when peritonitis is secondary to inflammatory disease, the onset is less rapid with the initial features being those of the underlying disease - poorly localised (irritation of visceral peritoneum) then moving to one point on abdomen and becoming localised (when it begins to irritate the parietal peritoneum) - lying still; people with peritonitis want to stay still - speedbumps are very painful for people with peritonitis - pain relieved by resting hands on abdomen; thereby stopping movement of peritoneum and thus pain - rigid abdomen
267
how is peritonitis diagnosed?
- blood test: • to monitor/confirm infection: raised white cell count and CRP • serum amylase to exclude acute pancreatitis • hCG: to differentiate from abdominal pain in pregnancy - erect CXR to see free air under diaphragm which indicates performed colon - abdominal X-ray to exclude bowel obstruction and foreign body as cause of abdominal pain - CT abdomen to exclude ischaemia as cause of pain
268
what is the treatment of peritonitis?
- ABC (airways, breathing, circulation) - treat underlying cause and treat early - insertion of nasogastric tube - IV fluids - IV antibiotics e.g. cefuroxime and metronidazole - surgery: • peritoneal lavage of the abdominal cavity • specific treatment of the underlying condition
269
what are the complications of peritonitis?
* delay in treatment can produce toxaemia and septicaemia which may lead to multi-organ failure * local abscess formation can occur and should be suspected if a patient continues to remain unwell post-op, with a swinging fever, high white cell count and continuing pain * abscesses are commonly pelvic or subphrenic and can be localised using ultrasound and CT * kidney failure * paralytic ileus
270
what is paralytic ileus?
- complication of peritonitis - peristaltic waves in colon stop leading to fluid stagnation - causes a distended gut and bloating which puts pressure on stomach and interferes with diaphragm and thus breathing - causes patient to breathe less deeply which promotes infection as bacteria can remain deep in lungs as they are not exhaled
271
what is volvulus? where can it occur?
• complete twisting of a loop of intestine around its mesenteric attachment • can occur at the stomach, small intestine, caecum, transverse colon and sigmoid colon
272
how does the GI tract develop? when can volvulus occur?
• in the 4th week of gestation the GI tract is a straight line • at the 8th week the midgut rotates and become fixed to the posterior wall • any arrest in the development at any stage will result in the narrowing of the mesenteric base which impairs fixation onto the posterior abdominal wall thereby increasing risk of volvulus
273
what is the epidemiology of volvulus?
- equal gender prevalence | - presents in children and babies commonly
274
what is the clinical presentation of volvulus?
- bilious vomiting (green and yellow) - failure to thrive - anorexia - constipation - bloody stools - abdominal pain - malnutrition - immunodeficiency - volvulus of stomach
275
what is the classical triad of GI obstruction in volvulus?
- vomiting (then retching) - pain - failed attempts to pass an NG (naso-gastric) tube
276
what are features of volvulus of the stomach?
• quite rare • regurgitation of saliva also occurs • dysphagia and noisy gastric peristalsis (relieved by lying down) may occur in chronic volvulus • classical triad of GI obstruction features: - vomiting (then retching) - pain - failed attempts to pass an NG tube
277
what are differential diagnoses of volvulus?
- other causes of acute obstruction | - appendicitis, cholecystitis, constipation, gastroenteritis, GORD, hepatitis, peptic ulcer and pancreatitis
278
how is volvulus diagnosed?
- AXR: • sigmoid volvulus will show an inverted U shape loop of bowel that looks a bit like a coffee bean - ultrasound - MRI and CT
279
what are treatments of volvulus?
- surgical correction e.g. Ladd’s procedure (anti-clockwise rotation to correct error) - non-surgical: GI compression with a naso-gastric tube
280
what are some complications of volvulus treatment?
* intestinal ischaemia, mucosal necrosis and sepsis * perforation, peritonitis and death * malabsorption * growth retardation
281
what is the epidemiology of oesophageal tumours?
* sixth most common cancer worldwide * squamous cell carcinoma occurs in the middle third (40% of all oesophageal cancer) and in the upper third (15%) of the oesophagus * adenocarcinomas occur in the lower third of the oesophagus and at the cardia and represent around 45% of tumours * carcinoma of the oesophagus occurs mainly in those aged 60-70 yrs
282
what is the epidemiology of squamous cell carcinoma?
* occurs in the middle third and upper third of the oesophagus * common in Ethiopia, China, South and East Africa * in the UK the incidence is 5-10 per 100,000 * incidence is decreasing in contrast to adenocarcinoma * more common in males than females
283
what are the causes of squamous cell carcinoma?
- high levels of alcohol consumption - achalasia (disorder where oesophagus has reduced/no ability to do peristalsis and transport food down) - tobacco use - obesity due to increased reflux - smoking - low fruit and veg consumption - diets rich in fibre, carotenoids (carrots), folate and vitamin C decrease risk
284
what is the epidemiology of adenocarcinoma in the oesophagus?
* arises in the lower third of the oesophagus and accounts for 45% of all oesophageal tumours * primarily arises in the columnar-lined epithelium in the lower oesophagus * in Barrett’s oesophagus, recurrent acid exposure results in the squamous epithelium being replaced by metaplastic columnar mucosa * incidence is increasing in western countries * previous reflux symptoms increase risk up to 8x
285
what are the causes of adenocarcinoma in the oesophagus?
- smoking - tobacco - GORD - obesity due to increased reflux
286
what are risk factors for oesophageal tumours?
- alcohol - smoking - obesity, since increased reflux - achalasia - obesity - diet low in Vit A and C - Barretts oesophagus
287
what occurs in Barrett's oesophagus?
recurrent acid exposure results in the squamous epithelium being replaced by metaplastic columnar mucosa
288
where do oesophageal tumours occur?
- squamous cell carcinoma occurs in the upper 2/3rds of the oesophagus - adenocarcinoma occurs in the lower 1/3rd of the oesophagus
289
what is the clinical presentation of oesophageal tumours?
- most patients with upper GI cancer have no physical signs and when the cancer is found it is extremely advanced - progressive dysphagia: • initially there is difficulty in swallowing solids but dysphagia for liquids follows within weeks • if there is dysphagia to solids and liquids from the start this indicates benign - weight loss - lymphadenopathy - anorexia - pain due to impaction of food or infiltration of cancer into adjacent structures - oesophageal obstruction eventually causes difficulty in swallowing saliva, coughing and aspiration into the lungs - signs from upper third of oesophagus: hoarseness and cough
290
how are oesophageal tumours diagnosed?
- pesophagoscopy with biopsy: to confirm diagnosis with histological proof of carcinoma - barium swallow: to see strictures - CT scan/MRI/PET for tumour staging - note: PET is more sensitive in detecting metastases
291
what is treatment of oesophageal tumours?
- surgical resection: • best chance of cure if tumour has not infiltrated outside the oesophageal wall (stage 1) • combined with chemotherapy (neoadjuvant chemotherapy) before surgery (improves outcomes) +/- radiotherapy - if locally incurable or metastatic then systemic chemotherapy is used (stage 2 and 3) - treatment of dysphagia - palliative care may be only option - survival rates as a whole are low
292
what is the treatment of dysphagia that is due to oesophageal tumours?
* endoscopic insertion of expanding metal stent across tumour to ensure oesophageal patency * laser and alcohol injections to cause tumour necrosis and increase lumen size
293
what is the epidemiology of benign oesophageal tumours? what are the different types? which is the most common type?
- account for 1% of all oesophageal tumours - leiomyomas are most common - papillomas - fibrovascualr polyps - haemangiomas - lipomas
294
what is the pathophysiology of benign oesophageal tumours?
- leiomyomas are smooth muscle tumours arising from the oesophageal wall - they are intact, well encapsulated and are within the overlying mucosa - slow growing
295
what are clinical features of benign oesophageal tumours?
- usually asymptomatic, found incidentally on barium swallow - dysphagia - retrosternal pain - food regurgitation - recurrent chest infections
296
how are benign oesophageal tumours diagnosed?
- endoscopy - barium swallow - biopsy to rule out malignancy
297
what is the treatment of benign oesophageal tumours?
- endoscopic removal | - surgical removal of larger tumours
298
what is the epidemiology of gastric adenocarcinomas?
- gastric cancer is the 4th most common cause of cancer worldwide - more common in males than females - incidence increases with age; peak age is 50-70 yrs - rare under age of 30 - highest incidence found in Eastern Asia, Eastern Europe and South America - incidence of adenocarcinoma in the body and distal stomach is falling
299
what are the different stages of gastric adenocarcinoma?
1. normal gastric mucosa 2. Helicobacter pylori infection 3. acute gastritis 4. chronic active gastritis 5. atrophic gastritis 6. intestinal metaplasia 7. dysplasia 8. advanced gastric cancer
300
what are the main behavioural, bacterial, dietary and genetic causes of gastric adenocarcinoma?
• smoking • Helicobacter pylori infection: - H.pylori infection causes chronic gastritis which eventually leads to atrophic gastritis and premalignant intestinal metaplasia • dietary factors: - high salt and nitrates increase risk - non-starchy vegetables, fruit, garlic and low salt decrease risk • loss of p53 (tumour suppressor gene) and APC genes • first degree relative with gastric cancer; CDH1 gene • pernicious anaemia increases risk due to accompanying atrophic gastritis
301
what are the 2 main types of gastric adenocarcinoma?
intestinal and diffuse
302
what is the pathophysiology of intestinal gastric adenocarcinoma?
- well formed and differentiated glandular structures - tumours are polypoid or ulcerating lesions with heaped-up, rolled edges - intestinal metaplasia is seen in the surrounding mucosa, often with H. pylori - this type is more likely to involve the distal stomach and occur in patients with atrophic gastritis - has a strong environmental association
303
what is the pathophysiology of diffuse gastric adenocarcinoma?
- poorly cohesive undifferentiated cells - tend to infiltrate the gastric wall - can involve any part of the stomach, especially the cardia - has a worse prognosis than intestinal
304
what is the clinical presentation of gastric adenocarcinoma?
- most patients with carcinoma of the stomach have advanced disease at the time of presentation - epigastric pain that is indistinguishable from peptic ulcer disease (may be relieved by food and antacids), pain is constant and severe - nausea, anorexia - weight loss - vomiting is frequent and can be severe if tumour encroaches on the pylorus - dysphagia if tumour is in fundus - anaemia from occult blood loss (however haematemesis is rare) - liver metastasis resulting in jaundice - metastases also occur in bone, brain and lung - palpable lymph node in supraclavicular fossa - Virchow’s node - usually on left side
305
how is gastric adenocarcinoma diagnosed?
- gastroscopy and biopsy to histologically confirm adenocarcinoma: • positive biopsies can be obtained in almost all cases of obvious carcinoma, but a negative biopsy does not rule out diagnosis • thus 8-10 biopsies are taken - endoscopic ultrasound to evaluate the depth of invasion - CT/MRI for staging - PET scan to identify metastases
306
what is the treatment of gastric adenocarcinoma?
- nutritional support - surgery and combination chemotherapy; epirubicin + cisplatin + 5-fluorouracil (given around same time as surgery) and post-op radiotherapy
307
what is ECF chemo?
epirubicin + cisplatin + 5-fluorouracil
308
what is the epidemiology of small intestine tumours?
- quite a rare place for cancer to develop; 1% of all malignancies - adenocarcinoma is the most common tumour of the small intestine, accounting for up to 50% of primary tumours - lymphomas (Non-Hodgkin's type) are most frequently found in the ileum and are less common than adenocarcinomas
309
what are risk factors for small intestine tumours?
- Coeliac disease | - Crohn’s disease
310
what is the clinical presentation of small intestine tumours?
- pain, diarrhoea, anorexia, weight loss, anaemia | - may be a palpable mass
311
how are small intestine tumours diagnosed?
- ultrasound - endoscopic biopsy to histologically confirm diagnosis - CT scan: may show small bowel wall thinning and lymph node involvement; seen in lymphoma
312
what is the treatment of small intestine tumours?
- surgical resection | - radiotherapy
313
what is a colonic polyp?
* a colonic polyp is an abnormal growth of tissue projecting from the colonic mucosa * polyps range from a few millimetres to several centimetres and are single or multiple
314
what are features of adenomas as a type of colonic polyp?
- adenomas are the precursor lesion in most cases of colon cancer - they are a benign, dysplastic tumour of columnar cells or glandular tissue - vast majority are sporadic and not inherited
315
what are clinical features of colonic polyps?
* most polyps are asymptomatic and found by chance * adenoma presence increases with age and is rare before 30 yrs * polyps are removed at colonoscopy to reduce development into cancer risk * polyps in the rectum or sigmoid colon often present with bleeding
316
what are types of inherited colonic polyps?
- familial adenomatous polyposis (FAP) | - Lynch syndrome (Hereditary Non-Polyposis Colon Cancer)
317
what is familial adenomatous polyposis (FAP)? what is the pathophysiology?
• autosomal dominant condition arising from a mutation in the APC gene • characterised by the presence of hundreds to thousands of colorectal and duodenal adenomas • develop adenomas at 16 and cancer develops at 39 • often given prophylactic colectomy and ileorectal anastamosis - APC binds to GSK and beta catenin (normally keeps beta catenin levels down) - misfolded/no protein at all -> no binding to beta catenin and it binds to DNA -> epithelial proliferation -> adenoma formation
318
what is Lynch syndrome?
Hereditary Non-Polyposis Colon Cancer (HNPCC) • polyps are formed in the colon and may rapidly progress to colon cancer • autosomal dominant condition caused by a mutation in one of the DNA mismatch repair genes, usually hMSH2 or hMSH1 • these genes are responsible for maintaining the stability of DNA during replication; this defect causes naturally occurring, highly repeated, short DNA sequences known as micro satellites that are shorter or longer than normal • this increases the risk of DNA damage in replication and thus colorectal carcinoma development • thus instead of taking 10-15 years for polyps to develop into colorectal carcinoma it occurs more rapidly
319
what is the epidemiology of colorectal carcinoma?
- usually adenocarcinoma - majority occur in distal colon - majority of presentations are in those over 60 yrs - more common in males than females - more common in Western countries than in Asia or Africa - 3rd most common cancer worldwide
320
what are risk factors for colorectal carcinoma?
- increasing age - low fibre diet - saturated animal fat and red meat consumption - sugar consumption - colorectal polyps - alcohol and smoking - obesity - adenomas - ulcerative colitis - family history - genetic predisposition (FAP and HNPCC)
321
how can the risk for colorectal carcinoma be reduced?
vegetables, garlic, milk, exercise, low-dose aspirin
322
what is the progression of colorectal carcinoma?
normal epithelium → adenoma → colorectal adenocarcinoma -> metastatic colorectal adenocarcinoma
323
what is the pathophysiology of colorectal carcinoma?
- nearly all are adenocarcinoma - polypoid mass with ulceration - spreads by direct infiltration through the bowel wall then spreads to lymphatic and blood vessels and metastases to liver and lung
324
what is the clinical presentation of colorectal carcinoma?
- majority distributed in distal colon | - the closer the cancer is to the outside the more visible blood and mucus will be
325
what is the clinical presentation of right sided colorectal carcinoma?
* usually asymptomatic until they present with iron deficiency anaemia due to bleeding * may present with a mass * weight loss * low haemoglobin * abdominal pain
326
what is the clinical presentation of left sided and sigmoid carcinoma?
* change of bowel habit with blood and mucus in stools * diarrhoea * alternation constipation and diarrhoea * thin/altered stool * blood in/with stools
327
what is the clinical presentation of rectal carcinoma?
* rectal bleeding and mucus | * when cancer grows patient will have thinner stools and tenesmus (cramping rectal pain)
328
what is the emergency presentation of colorectal carcinoma?
obstruction (20%)
329
what are the 4 cardinal signs of bowel obstruction?
* absolute constipation * colicky abdominal pain * abdominal distension * vomiting (faeculent)
330
what are the differential diagnoses of colorectal carcinoma?
anorectal pathology: • haemorrhoids, anal fissure, anal prolapse colonic pathology: • diverticular disease, IBD, ischaemic colitis small intestine and stomach pathology: • massive upper GI bleed - haematochezia • Meckel’s diverticulum
331
how is colorectal carcinoma diagnosed?
- faecal occult blood (FOB); used in screening - tumour markers e.g. CEA - not specific enough, useful for follow up and screening - colonoscopy - double contrast barium enema - CT colonoscopy - MRI to determine spread, done in all rectal cancers
332
what are features of colonoscopy in diagnosing colorectal carcinoma?
* gold standard * allows for biopsy and the removal of polyps * uncomfortable so usually sedation used * risk of perforation which comes with a 50% risk of needing a stoma and a 20% risk of death with procedure
333
what are features of double contrast barium enema in diagnosing colorectal carcinoma?
* 2nd line alternative to colonoscopy * doesn't require sedation * avoid perforation risk * more limited in detecting small lesions
334
what are features of CT colonoscopy in diagnosing colorectal carcinoma?
* 2nd line alternative to colonoscopy in the elderly * no sedation and avoids perforation risk * limited in detecting small lesions but good at excluding cancer
335
what is the Duke's classification of colorectal carcinoma?
- A = limited to muscularis mucosae; 95% 5 yr survival - B = extension through muscularis mucosae (not lymph nodes); 75% 5 yr survival - C = involvement of regional lymph nodes; 35% 5 yr survival - D = distant metastases; 25% 5 yr survival
336
what is the TNM system to classifying cancer?
T • refers to the primary tumour and is suffixed by a number that denotes tumour size • the number varies according to the organ harbouring the tumour N • refers to lymph node status and is suffixed by a number that denotes the number of lymph nodes or groups of lymph nodes containing metastases M • refers to the anatomical extent of distant metastases
337
what is the treatment of colorectal carcinoma?
- surgery - endoscopic stenting - radiotherapy - chemotherapy - other treatments
338
how is surgery used to treat colorectal carcinoma?
• only chance at cure • only indicated if there is no metastasis • open: - right hemicolectomy - transverse colon – extended right hemicoectomy - left sided hemicolectomy - sigmoid colectomy - low sigmoid, high rectal – anterior resection • laparoscopic: - less time in hospital, just as safe and same results
339
what are features of endoscopic stenting used in colorectal cancer?
* for palliation in malignant obstruction | * decreases need for colostomy
340
what are features of radiotherapy used in colorectal cancer?
* palliation for colonic cancer | * used pre-op in rectal cancer
341
how can colorectal cancer be treated differently?
• polyp cancers - removed with colonoscopy (no surgery needed) • rectal cancer: - hard to excise - identify position with MRI and if early case can be removed with low anterior resection - if more advanced then treated aggressively with chemotherapy pre-op (neoadjuvant chemo) to shrink tumour
342
what is the epidemiology of hepatocellular carcinoma?
- 5th most common cancer worldwide - accounts for 90% of liver primaries - common in China - more common in males than females
343
what are risk factors of hepatocellular carcinoma?
- carriers of HBV and HCV have an extremely high risk of developing HCC - associated with cirrhosis such as alcohol cirrhosis, NAFLD and haemochromatosis
344
what is the pathophysiology of hepatocellular carcinoma?
- tumour is either single or occurs as multiple nodules throughout the liver - consists of cells resembling hepatocytes - it can metastasise via the hepatic or portal veins to the lymph nodes, bones and lungs - can be benign or malignant, but most common are malignant
345
what is the clinical presentation of hepatocellular carcinoma?
- weight loss - anorexia - fever - fatigue - jaundice - ache in the right hypochondrium - ascites - rapid development of these features in a cirrhotic patients is an indicator of HCC - on examination an enlarged, irregular, tender liver may be felt
346
how is hepatocellular carcinoma diagnosed?
- serum alpha-fetoprotein may be raised - ultrasound scan shows filling defects in 90% of cases - enhanced CT: • to identify HCC but hard to confirm diagnosis if the lesion is less than 1cm • usually used to confirm diagnosis if lesion is large enough - liver biopsy: • under ultrasound guidance to confirm diagnosis • used less now due to potential seeding of tumour along biopsy tract and since imaging is better
347
how is hepatocellular carcinoma treated?
- surgical resection of isolated lesion | - liver transplant is only chance for cure
348
how is hepatocellular carcinoma prevented?
* persistent HBV infection, usually acquired after perinatal infection is a high risk factor for HCC in many parts of the world such as South-east Asia * widespread vaccination against HBV can be used to reduce HCC incidence
349
what is cholangiocarcinoma? what is its epidemiology?
- cancer of the biliary tree | - responsible for 10% of liver primaries
350
what are risk factors for cholangiocarcinoma?
- associated with infestation with parasitic worms (flukes) e.g. Clonorchis sinensis - biliary cysts - inflammatory bowel disease e.g. UC and Crohn’s
351
what is the pathophysiology of cholangiocarcinoma?
- usually slow growing | - most are distal extrahepatic or perihilar
352
what is the clinical presentation of cholangiocarcinoma?
- fever - abdominal pain +/- ascites - malaise - jaundice - raised alkaline phosphate
353
what is the treatment of cholangiocarcinoma?
- surgical resection is rarely possible and patients die within 6 months - liver transplant is contraindicated
354
what is the most common benign tumour in the liver?
haemangioma
355
what are features of haemangioma?
- most common benign tumour in the liver - usually small and single but can be multiple and large - usually found on ultrasound, CT or MRI and have characteristic appearances - require no treatment
356
what are features of hepatic adenoma?
- benign - common - associated with oral contraceptives, anabolic steroids and pregnancy - can present with abdominal pain or intraperitoneal bleeding - surgical resection is only required for symptomatic patients with tumours larger than 5cm in diameter
357
what are non-infective causes of diarrhoea?
- neoplasm - hormonal - inflammatory - radiation - irritable bowel - chemical - anatomical
358
what are causative organisms of diarrhoea?
- Rotavirus - Shigella - E.Coli 0157 - Salmonella Typhi - Salmonella Paratyphi - Hepatitis A - Hepatitis E - Vibrio cholerae
359
what are features of Norovirus?
- major cause of winter vomiting - mainly occurs in the winter - mainly causes vomiting - may cause diarrhoea, nausea, cramps, headache, fever, chills, myalgia - lasts 1-3 days - immunity is short lived
360
what does Clostridium difficile cause in hospitalised patients?
- antiobiotic associated diarrhoea - antibiotic associated colitis - pseudomembranous colitis
361
what is the epidemiology of Clostridium difficile?
- asymptomatic carriage in 2-3% of healthy adults, 2/3 babies and 36% of hospital patients - spread by faeco-oral route directly or through spores in the environment - asymptomatic carriers without diarrhoea unlikely to spread it - 80% of symptomatic cases in people >65 years - 20% of antibiotic associated diarrhoea
362
what are at risk groups for diarrhoea?
- persons of doubtful personal hygiene or with unsatisfactory hygiene facilities at home, work or school - children at preschool or nursery - work involves preparing or serving unwrapped/uncooked food - HCW/social care staff working with vulnerable people
363
where can secondary liver tumours come from?
- particularly from: • GI tract (due to distribution of the portal blood supply) • breast • bronchus - secondary liver tumours are usually multiple
364
what is the clinical presentation of secondary liver tumours?
- variable - weight loss - malaise - upper abdominal pain - hepatomegaly with/without jaundice
365
what is the diagnosis of secondary liver tumours?
- ultrasound is primary investigation with CT or MRI to define metastases and look for a primary - serum alkaline phosphatase is raised
366
what is the treatment of secondary liver tumours?
- depends on site of the primary and the burden of liver metastases - removal of primary tumour and hepatic resection - chemotherapy is used, particularly with breast cancer
367
what is the epidemiology of pancreatic adenocarcinoma?
- 99% of pancreatic cancer occurs in the exocrine (part that releases pancreatic juice) component of the pancreas - UK incidence is rising - more common in males than females - typical patient is male above 60 yrs - rare in those younger than 40 yrs - majority are adenocarcinoma and the large majority are of ductal origin
368
what are risk factors for pancreatic adenocarcinoma?
- smoking is associated with a two-fold risk increase - excessive intake of alcohol or coffee - excessive use of aspirin - diabetes - chronic pancreatitis - genetic mutation predisposing to pancreatic cancer; presence of PRSS-1 mutation - family history
369
what is the pathophysiology of pancreatic adenocarcinoma? where do they arise from?
- originates in the ductal epithelium and evolves from pre-malignant lesions to full invasive cancer - most ductal adenocarcinomas metastasise early and thus present late - 60% arise in the pancreatic head - 25% arise in the body - 15% in the tail
370
what is the clinical presentation of pancreatic adenocarcinoma?
- anorexia - weight loss - diabetes - acute pancreatitis - head of pancreas: painless obstructive jaundice; pale stools and dark urine - body and tail of pancreas: epigastric pain that radiates to the back and is relieved by sitting forward
371
what is the clinical presentation of pancreatic adenocarcinoma that is in the head of the pancreas?
painless obstructive jaundice - pale stools and dark urine
372
what is the clinical presentation of pancreatic adenocarcinoma that is in the body and tail of the pancreas?
epigastric pain that radiates to the back and is relieved by sitting forward
373
what are the differential diagnoses of pancreatic adenocarcinoma?
- diagnosis should not be difficult in the presence of painless jaundice or epigastric pain radiating into the back with progressive weight loss - however, many present with minor symptoms such as pain, changing bowel habit and weight loss - abdominal CT should be done if pancreatic cancer is suspected - IgG4-related autoimmune pancreatitis
374
what is the diagnosis of pancreatic adenocarcinoma?
- patients with pancreatic adenocarcinoma frequently present quite late stage that often cannot be cured - cholestatic jaundice is non-specific but helps assess prognosis - transabdominal ultrasound and CT to find pancreatic mass +/- dilated biliary tree; they can guide biopsy and help with staging prior to surgery
375
what is treatment of pancreatic adenocarcinoma?
- 5 year survival is 3% - surgery: • consider pancreato-duodectomy if fit and no metastases • high post-op morbidity • post-op chemotherapy delays disease progression - palliative therapy: • palliation of jaundice using stenting • opiates for the pain • nutritional supplementation
376
what is the definition of a hernia?
the profusion of a viscus (organ) or part of a viscus through a defect of the walls of the cavity containing it into an abnormal position; can be reducible or irreducible
377
what are types of irreducible hernias?
- obstructed: intestine is obstructed within the hernia due to pressure from the edges of the hernia, but blood flow is maintained - incarcerated: contents of the hernial sac are stuck inside by adhesions e.g. adhesions between the intestines and hernial sac - strangulated: blood supply of the sac is cut off resulting in ischaemia +/ gangrene/perforation of the hernial contents - patent becomes toxic and requires urgent surgery
378
what are the contents of an inguinal hernia?
external and internal and cremasteric fascia
379
what are the arteries of the spermatic cord in an inguinal hernia?
- testicular artery - cremasteric artery - artery of the Vas
380
what are the veins of the spermatic cord in an inguinal hernia?
- pampiniform plexus of testicular veins - cremasteric vein - vein of the Vas
381
what are the nerves of the spermatic cord in an inguinal hernia? what do they supply?
- ilioinguinal nerve: skin sensation to anterior 1/3rd of external genitalia - genitofemoral nerve: to cremasteric muscle - sympathetic nerves: to vas and testicular pain
382
what are the 'three others' of the spermatic cord in an inguinal hernia?
- vas deferens: duct that transports sperm from the epididymis to the ejaculatory ducts - lymph vessels - tunica vaginalis: serous membrane covering of the testes derived from the processus vaginalis (pathway of descent for testes during embryological development)
383
what is the epidemiology of inguinal hernia?
- commonest type of hernia - more common in males than females - two types; indirect and direct - indirect is more common than direct - account for 70% of all abdominal hernias - most common in men over 40 - they pass through the internal inguinal ring and, if large, out through the external ring
384
what are risk factors for inguinal hernias?
- male - chronic cough - constipation - urinary obstruction - heavy lifting - ascites - past abdominal surgery
385
what are features of the inguinal canal?
* a short passage (5cm) that extends medially and inferiorly, through the inferior part of the abdominal wall * extends from the deep inguinal ring to the superficial ring * it acts as a pathway by which structures can pass from the abdominal wall to the external genitalia * it is a potential weakness in the abdominal wall and therefore is a common site of herniation
386
what are features of a direct inguinal hernia?
* less common (20%) * where the peritoneal sac enters the inguinal canal through the posterior wall of the inguinal canal, medial to the inferior epigastric vessels * rarely strangulate * reduce easily
387
what are features of an indirect inguinal hernia?
* more common (80%) * where the peritoneal sac enters the inguinal canal through the deep inguinal ring * follows the path of the inguinal canal, passes through the deep inguinal ring and if large then out through the superficial inguinal ring * lateral to the inferior epigastric vessels * can strangulate
388
what is the clinical presentation of inguinal hernia?
- bulging associated with coughing or straining (bowel movement, heavy lifting) - appearance of lump - rarely painful - patient can usually reduce the hernia themselves - if painful then indicates strangulation
389
what are differential diagnoses of inguinal hernias?
- femoral hernia - epididymitis - testicular torsion - groin abscess - aneurysm - hydrocele - undescended testes
390
what is the diagnosis of inguinal hernias?
look for lump
391
what is the surgical treatment of inguinal hernias?
- only if very symptomatic - prosthetic mesh, open repair, laparoscopy - preop: diet and stop smoking - may recur
392
what happens in a femoral hernia?
bowel comes through the femoral canal below the | inguinal ligament
393
what is the epidemiology of a femoral hernia?
- less common than inguinal hernia - more common in females than males - occur in middle age and elderly
394
what is the pathophysiology of femoral hernias?
- bowel enters the femoral canal, presenting as a mass in the upper medial thigh or above the inguinal ligament where it points down the leg, unlike an inguinal hernia which points to the groin - likely to be irreducible and to strangulate due to the rigidity of the canal’s borders - the neck of the hernia is felt inferior and lateral to the pubic tubercle (inguinal hernias are superior and medial to this point)
395
what are differential diagnoses of femoral hernias?
- inguinal hernia - lipoma - femoral aneurysm - psoas abscess - saphena varix (dilation of saphenous vein at junction of femoral vein in groin)
396
what is the treatment of femoral hernias?
- surgical repair - herniotomy; ligation (stops bleeding once sac removed) and excision of the sac - herniorrhaphy; repair of the hernial defect
397
what occurs in an incisional hernia?
* occurs when tissue protrudes through a surgical scar that is weak * are a complication of abdominal surgery * can occur anywhere where there is an incision and follows a breakdown of muscle closure after surgery * if obese then repair is more difficult
398
what are risk factors for incisional hernias?
- emergency surgery - wound infection post op - persistent coughing and heavy lifting - poor nutrition
399
what is the epidemiology of hiatus hernias?
30% of patients are above 50, especially obese women
400
what are types of hiatus hernias?
- sliding hiatus hernia (80%) | - rolling or para-oesophageal hiatus (20%)
401
what are features of sliding hiatus hernias?
- where the gastro oesophageal junction and part of the stomach ‘slides’ up into the chest via the hiatus so that it lies above the diaphragm - acid reflux often happens as the lower oesophageal sphincter becomes less competent in many cases
402
what are features of rolling or paraoesophageal hiatus?
- where the gastro-oesophageal junction remains in the abdomen but part of the fundus of the stomach prolapses through the hiatus alongside the oesophagus - note: as the gastro-oesophageal junction remains intact, reflux is uncommon
403
what are clinical features of hiatus hernias?
50% have symptomatic GORD
404
what is the diagnosis of hiatus hernias?
- barium swallow confirms diagnosis | - upper GI endoscopy to visualise the mucosa but cannot exclude hiatus hernia
405
what is treatment of hiatus hernias?
- lose weight - treat reflux symptoms - surgically treat to prevent strangulation
406
what is a liver abscess? what are different types?
pus-filled mass inside liver post-infection, appendicitis or haematogenous spread (via portal vein) - pyogenic (bacterial) abscess - amoebic abscess
407
what is the aetiology of pyogenic (bacterial) abscess?
- unknown in many cases - in the elderly, biliary sepsis is a common cause - trauma - haematogenous; bacteraemia from portal vein (mesenteric infections) - infection of tumour or cyst - direct extension e.g. empyema of gall bladder or perinephric abscess - pathogens
408
what pathogens can cause pyogenic (bacterial) liver abscesses?
* commonest sites from biliary tract, dental source, renal or intestinal * E.coli (most common and gram-negative) * Streptococcus milleri * Klebsiella pneumoniae (gram-negative) * Bacteroids spp. and other anaerobes
409
what is the clinical presentation of pyogenic (bacterial) liver abscess?
- fever - vomiting - weight loss - right upper quadrant abdominal pain +/- pleuritic/right shoulder pain - tender hepatomegaly +/- obstructive jaundice
410
what is the diagnosis of pyogenic (bacterial) liver abscess?
- blood culture - serum alkaline phosphatase, ESR and CRP raised - CT abdomen - useful if multiple lesions - ultrasound - to detect and sample abscess
411
what is the treatment of pyogenic (bacterial) liver abscess?
- aspiration of abscess under ultrasound control - antibiotics - surgery if resolution is slow or difficult and done on source e.g. biliary, gut, dental etc
412
what antibiotics are used to treat pyogenic (bacterial) liver abscess?
- Co-amoxiclav (amoxicillin + clavulinic acid) - Piperacillin + Tazobactam - Gentamicin - Meronidiazole
413
what is amoebic liver abscess caused by?
Entamoeba histolytica
414
what is the pathophysiology of amoebic liver abscess?
- Entamoeba histolytica can be carried from the bowel to the liver in the portal venous system - this results in portal inflammation, with the development of multiple microabscesses and, eventually, single or large abscesses - often a single mass in the right lobe of liver containing ‘anchovy sauce’ pus
415
what is the clinical presentation of amoebic liver abscess?
- onset is usually gradual but may be sudden - fever - abdominal pain - anorexia - weight loss - malaise - tender hepatomegaly - signs of effusion or consolidation in the base of the right side of the chest
416
what is the diagnosis of amoebic liver abscess?
- serological test for amoeba e.g. haemagglutination, ELISA:is always positive but remains positive even after clinical cure so do not indicate current disease - cyst aspiration shows ‘anchovy sauce pus’; diagnostic
417
what is the treatment of amoebic liver abscess? what antibiotic is given?
- metronidazole for 10 days - aspiration for those failing to respond - complications: rupture or secondary infection septicaemia
418
what is the definition of diarrhoea? how is acute and chronic diarrhoea defined?
- the abnormal passage of loose or liquid stool more than 3 times daily - acute diarrhoea is defined as that lasting less than 2 weeks - chronic diarrhoea is defined as lasting more than 2 weeks
419
what are the causes, diagnosis and treatments of acute diarrhoea?
- usually due to infection e.g. travellers diarrhoea - flexible sigmoidoscopy with colonic biopsy is performed if symptoms persist and no diagnosis has been made - treatment is symptomatic to maintain hydration with anti-diarrhoeal agents (Loperamide hydrochloride) for short-term relief and antibiotics for specific indications
420
what is the diagnosis/causes of chronic diarrhoea?
- defined as diarrhoea persisting for more than 2 weeks - organic causes (associated with changes in the structure of an organ or tissue resulting in symptoms; increased stool weights) must be differentiated from functional causes (conditions in which there is no physical cause for symptoms - frequent passage of low volume and weight stools) such as irritable bowel syndrome (IBS) - sometimes faecal markers of intestinal inflammation are used to differentiate functional disorders from organic disease
421
what features of diarrhoea will point to certain causes?
- sudden onset of bowel frequency associated with crampy abdominal pains and a fever will point to an infective cause - bowel frequency with loose, blood-stained stools will point to an inflammatory cause - passage of pale, offensive stools that float often accompanied by a loss of appetite and weight loss point to steatorrhoea
422
what is decreased stool consistency in diarrhoea caused by?
- water - fat (steatorrhoea) - inflammatory discharge
423
what are features of osmotic diarrhoea?
• large quantities of non-absorbed hypertonic substances in the bowel draw fluid into the intestine • diarrhoea stops when the patient stops eating or the malabsorptive state is discontinued
424
what are causes of osmotic diarrhoea?
- ingestion of non-absorbable substances e.g. a laxative such as magnesium sulphate - generalised malabsorption so that high concentrations of solute remain in the lumen - specific malabsorptive defect e.g. disaccharide deficiency
425
what are features of secretory diarrhoea?
- microscopic colitis - there is active intestinal secretion of fluid and electrolytes as well as decreased absorption - continues even when the patient fasts
426
what are causes of secretory diarrhoea?
- enterotoxins e.g. E.coli and cholera toxin - bile salts in colon following ileal disease, resection or idiopathic bile acid malabsorption - fatty acids in colon following ileal resection
427
what are features of diarrhoea caused by fat (steatorrhoea)?
- characterised by increase gas, offensive smell and floating hard-to-flush stools - giardiasis and coeliac disease can cause steatorrhoea
428
what are features of diarrhoea caused by inflammatory discharge?
damage to the intestinal mucosal cell leads to loss of fluid and blood and defective absorption of fluid and electrolytes
429
what are causes of inflammatory discharge that causes diarrhoea?
- infective e.g. shigella or salmonella | - inflammatory e.g. UC or crohns
430
what is the epidemiology of infective diarrhoea?
- 2nd leading cause of death in children under 5 globally | - highest prevalence in South Asia and Africa
431
what are risk factors for infective diarrhoea?
- foreign travel - PPI or H2 antagonist use - crowded area - poor hygiene
432
what is the aetiology of infective diarrhoea in children?
rotavirus - leading cause of diarrhoea illness in young children, affects nearly all children by the age of 4
433
what is the aetiology of infective diarrhoea in adults?
norovirus, campylobacter
434
what is the aetiology of infective viral diarhhoea?
• 70% of all infectious diarrhoea in paediatric age group world • rotavirus: - most common in children - leading cause of diarrhoeal illness in young children and affects nearly all children by the age of 4 • norovirus: - most common among adults and 10% of all children cases - associated with; cruise ships, hospitals, restaurants - close proximity of people • adenovirus • astrovirus
435
what are bacterial causes of infective diarrhoea?
``` • Campylobacter jejuni: - most common cause of bacteria diarrhoea - associated with poultry • more common in children: - E.coli - Salmonella - Shigella spp. ```
436
what is the antibiotic rule of Cs for infective diarrhoea?
in general, antibiotics beginning with C can give rise to antibiotic induced Clostridium difficile diarrhoea: - Clindamycin - Ciprofloxacin (Quinolones) - Co-amoxiclav (Penicillins) - Cephalosporins
437
what is Clostridium difficile? how can it cause diarrhoea?
* gram positive spore forming bacteria * up to 5% have C.diff as part of normal flora * can give rise to pseudomembranous colitis where C.diff replaces the moral gut flora (when normal gut flora die due to antibiotic use), resulting in dangerous diarrhoea
438
what are risk factors for C. difficile leading to diarrhoea?
- elderly, antibiotics, long hospital admission, immunocompromised e.g. HIV - acid suppression: PPI or H2 receptor antagonist
439
what is treatment of C. difficile diarrhoea?
- metronidazole - oral vancomycin - rifampicin/rifaximin - stool transplant - stop C antibiotic
440
what are parasitic causes of infective diarrhoea?
* Giardia lamblia - most common * Entamoeba histolytica * Cryptosporidium
441
what is the clinical presentation of infective diarrhoea?
- diarrhoea: • blood usually indicates bacterial infection • salmonella, E.coli and shigella all cause bloody stools - vomiting - abdominal cramping - viral causes: fever, fatigue, headache, muscle pain - in general there is an incubation period of 12-72 hours post-infection
442
what are differential diagnoses of infective diarrhoea?
- appendicitis, volvulus, IBD, UTI, diabetes mellitus - pancreatic insufficiency, short bowel syndrome, coeliac disease - laxative abuse
443
what is the diagnosis of infective diarrhoea?
- blood - stools: stool culture if suspected bacteria, parasites or C.diff - sigmoidoscopy with biopsy
444
what is seen in the blood in infective diarrhoea?
* low MCV and/or iron deficiency e.g. coeliac disease or colon cancer * high MCV if alcohol abuse or decreased B12 absorption e.g. coeliac disease or crohn’s * raised white cell count if parasites * raised ESR and CRP indicate infection, crohn’s, UC or cancer
445
what is the treatment of infective diarrhoea?
- treat causes - oral rehydration and avoid high-sugar drinks in children (increases diarrhoea) - anti-emetics e.g. metoclopramide - antibiotics - anti-motility agents e.g loperamide hydrochloride
446
give 3 examples of proton pump inhibitors
- lansoprazole - omeprazole - pantoprazole
447
what are indications for proton pump inhibitors?
- first line for prevention and treatment of peptic ulcer disease - symptomatic relief of dyspepsia and GORD - eradication of H.pylori infection with antibiotics
448
what is the mechanism of action of proton pump inhibitors?
- reduces gastric acid secretion by irreversibly inhibiting H+/K+ ATPase in gastric parietal cells; this is the proton pump responsible for secreting H+ and generating gastric acid - suppresses gastric acid production significantly
449
what are adverse effects/contraindications to proton pump inhibitors?
- GI disturbances and headaches are common - increasing gastric pH may reduce body’s host defence against infection, slightly higher risk of C.diff - PPIs may disguise symptoms of gastric cancer - can increased risk of fracture in the elderly so use with care if osteoporosis present - PPIs, especially omeprazole can reduce antiplatelet effect of clopidogrel
450
give an example of a H2 receptor antagonist
ranitidine
451
what are indications for H2 receptor antagonists?
- treatment and prevention of gastric and duodenal ulcers and NSAID associated ulcers if PPIs are contraindicated - relief of symptoms of GORD and dyspepsia if mild
452
what is the mechanism of action of H2 receptor antagonists?
- acid is normally produced by the proton pump of the gastric parietal cell, which secretes H+ into the stomach lumen in exchange for drawing K+ in - proton pump is regulated by histamine which binds to H2 receptors on parietal cell and activates the pump - so blocking the receptor reduces the activation of the cell - H2 receptor antagonists reduce gastric acid secretion but does not completely suppress secretion as the proton pump can be stimulated by other pathways; PPIs produce more complete effect
453
what are adverse effects/contraindications to H2 receptor antagonists?
- possible bowel disturbance, headache or dizziness - reduce dose in renal impairment - watch for symptoms of gastric cancer as H2 antagonist can disguise these
454
give 2 examples of alginates/antacids
gaviscon, peptac
455
what are indications for alginates/antacids?
- for GORD disease or symptomatic relief of heartburn | - for short term relief of indigestion and dyspepsia
456
what is the mechanism of action for alginates/antacids?
- most often taken as a compound preparation of an alginate with one or more antacid such as calcium bicarbonate, magnesium or aluminium salts - alginates work to increase the viscosity of the stomach contents which reduces the reflux of the stomach acid into the oesophagus - after reacting with stomach acid they from a floating raft which separates the gastric contents from the gastro-oesophageal junction to prevent mucosal damage
457
what are adverse effects/contraindications to alginates/antacids?
- magnesium can cause diarrhoea and aluminium can cause constipation - sodium and potassium containing compounds should be used with caution in fluid overload or hyperkalaemia i.e. in renal failure - antacids may reduce the concentration of ACE inhibitors, antibiotics, PPIs, bisphosphonates and digoxin so take dose at different times
458
give 2 examples of antimotility drugs?
loperamide, codeine phosphate
459
what are indications for antimotility drugs?
as symptomatic treatment of diarrhoea, usually for irritable bowel syndrome or gastroenteritis
460
what is the mechanism of action of antimotility drugs?
- loperamide is an opioid but does not penetrate the CNS so has no analgesic effects, it is just an agonist of the opioid μ-receptors in the GI tract which increases non propulsive contractions of the gut smooth muscle but reduces peristaltic contractions - therefore transit of bowel content is slowed and anal sphincter tone is increased, and also more water is absorbed from faeces as there is more time for this to occur so stools are hardened - codeine phosphate has the same effect but also with analgesia
461
what are adverse effects/contraindications to antimotility agents?
- most side effects are of GI disturbance and are mild - should be avoided in acute ulcerative colitis where inhibition of peristalsis may result in megacolon and perforation, should also be avoided if there is risk of C.difficile or other bacterial infection
462
what is an examples of a bile acid drug?
ursodeoxycholic acid
463
what are indications for use of ursodeoxycholic acid?
- used in primary biliary cirrhosis | - reduction in liver biochemistry, jaundice, ascites and itching
464
what is the mechanism of action of ursodeoxycholic acid?
- ursodeoxycholic acid reduces cholesterol absorption and is used to dissolve cholesterol gallstones as an alternative to surgery (however these tend to recur so surgery still preferred) - normally in the body it helps regulate cholesterol by reducing the rate at which the intestine absorbs cholesterol molecules, while breaking up micelles containing cholesterol
465
what are the adverse effects/contraindications to ursodeoxycholic acid use?
- side effects include nausea, diarrhoea and very rarely gallstone calcification can occur - is contraindicated in gallbladder impairment, calcium gallstones and severe liver impairment - use with care if patient is taking oral contraceptives, antacids, immunosuppressants or lipid regulating drugs as it can decrease their effectiveness
466
what is the oesophagus? what is its function?
* the oesophagus is a muscular tube approximately 20cm long that connects the pharynx to the stomach just below the diaphragm * its only function is to transport food from the mouth to the stomach
467
what is the histology of the oesophagus?
the oesophagus is lined by stratified squamous epithelium, which extends distally to the squamocolumnar junction where the oesophagus joins the stomach, recognised endoscopically by a zigzag (‘Z’) line, just above the most proximal gastric folds
468
what is the structure of the oesophagus and its sphincters?
* the oesophagus is a muscular tube approximately 20cm long that connects the pharynx to the stomach just below the diaphragm * the oesophagus is separated from the pharynx by the upper oesophageal sphincter (UOS), which is normally closed due to tonic activity of the nerves supplying the cricopharyngeus * the lower oesophageal sphincter (LOS) consists of a 2-4 cm zone in the distal end of the oesophagus that has a high resting tone and, assisted by the diaphragmatic sphincter, is largely responsible for the prevention of gastric reflux
469
what happens during swallowing?
1. during swallowing, the bolus of food is voluntarily moved from the mouth to the pharynx - this process is mediated by a complex reflex involving a swallowing centre in the dorsal motor nucleus of the vagus nerve in the brainstem 2. before the food can enter the oesophagus the upper oesophageal sphincter (UOS) relaxes immediately and as soon as the food has passed through it immediately closes 3. this reflex results in the initial relaxation of the smooth muscles of the lower oesophageal sphincter (LOS) followed by their contraction 4. pharyngeal and oesophageal peristalsis mediated by this swallowing reflex causes primary peristalsis 5. once in the oesophagus, the food moves towards the stomach by a progressive wave of muscle contractions that proceed along the oesophagus, compressing the lumen and forcing the food ahead - these are peristaltic waves and this is secondary peristalsis which arises as a result of stimulation by a food bolus in the lumen, mediated by a local intra-oesophageal reflex
470
what is the epidemiology of gastro-oesophageal reflux disease?
- GORD is common - it is said to exist when reflux of stomach contents (acid with/without bile) causes troublesome symptoms (defined as 2 or more heartburn episodes a week) and/or complications - reflux of gastric contents is normal but when there is prolonged contact of gastric contents with the mucosa this results in clinical symptoms - when there is prolonged reflux this may cause oesophagitis, stricture or Barrett’s oesophagus
471
what are causes of GORD?
* lower oesophageal sphincter hypotension * hiatus hernia * loss of oesophageal peristaltic function * abdominal obesity * gastric acid hypersecretion * slow gastric emptying * overeating * smoking * alcohol * pregnancy - results in increased abdominal pressure * fat, chocolate, coffee or alcohol ingestion * drugs e.g. antimuscarinic, calcium channel blockers and nitrates * systemic sclerosis
472
what are types of hiatus hernia that can cause GORD?
- sliding hiatus hernia (80%) | - rolling or paraoesophageal hiatus hernia (20%)
473
what is the pathophysiology of GORD?
- between swallows, the muscles of the oesophagus are relaxed except for the muscles of the upper and lower oesophageal sphincters - the LOS in the distal oesophagus remains closed and relaxes when swallowing is initiated - the relaxation of the LOS is part of normal physiology to allow food to enter the stomach and some transient lower oesophageal relaxations are normal - in GORD there are much more transient LOS relaxations as the LOS has reduced tone which allows gastric acid to flow back into the oesophagus - the LOS relaxes transiently, independently of a swallow, after meals
474
what factors contribute to GORD?
- increased mucosal sensitivity to gastric acid and reduced oesophageal clearance of acid contribute - delayed gastric emptying and prolonged post-prandial (after eating) and nocturnal reflux also contribute - a hiatus hernia can impair anti-reflux mechanisms and thus contribute
475
what is cholelithiasis?
formation of gallstones
476
label
477
where is gall bladder pain felt and why
in the skin of the right shoulder because the gall bladder is close to the diaphragm, any disease may cause the gall bladder to rub against the diaphragm, which is supplied by C3,4,5. - C3,4,5 cervical roots also supply the the dermatomes of the right shoulder
478
which artery does the cystic artery branch off
the right hepatic artery
479
structure and location of the gall bladder
* made of a body, fundus and neck * located * inferiorly and posterior to the liver * anterior to the first part of the duodenum and transverse colon
480
components of biliary tree
* common hepatic duct * cystic duct * common bile duct * pancreatic duct * hepatopancreatic ampulla of vater
481
how is cholesterol excreted
through bile this is the only mechanism of export
482
how is cholesterol transported in the blood
by lipoproteins
483
what is the main storage place of glycogen
the liver
484
function of the gall bladder
production AND concentration of bile Bilirubin and enterohepatic secretion of bile salts
485
what are the functions of albumin
1. maintains oncotic pressure 2. binding and transport or hydrophobic compounds - e.g. bilirubin, hormones and FAs 3. neutralisation of free radicals 4. anticoagulant effects
486
Why might liver failure result in oedema?
Liver failure may mean less albumin is produced and so you get hypoalbuminaemia. This means the capillary oncotic pressure is reduced and H2O accumulates in the interstitial space - oedema.
487
where is vitamin K absorbed
the intestine
488
why is vitamin K needed
production of clotting factors
489
what are the 2 essential proteins made by the liver
1. albumin 2. clotting factors
490
what are the pathways of the clotting cascade
1. intrinsic 2. extrinsic 3. common pathway
491
how is the intrinsic pathway triggered
exposure of endothelial collagen
492
how is the extrinsic pathway triggered
clotting factor 12 coming into contact with tissue factor
493
why is bile important
1. lipid digestion and absorption 2. cholesterol homeostasis 3. excretion of lipid-soluble xenobiotics, heavy metals and drug metabolites
494
bile is hydrophobic T/F
false it is amphiphilic
495
what are the functions of bile acids
* Induce bile flow (osmotic effect) & secretion of biliary lipids (PL and cholesterol) * Digestion of fats * Facilitating protein absorption by accelerating hydrolysis by pancreatic proteases * Cholesterol homeostasis * Antimicrobial – induces anti-microbial genes * Prevents calcium gallstones and oxalate renal stones.
496
6 functions of the liver
1. glucose and fat metabolism 2. defence against infection via kuppfer cells in reticuloendothelial system. 3. detoxification / metabolism 4. excretion 4. protein synthesis of albumin and clotting factors 5. oestrogen regulation
497
potential outcomes of liver dysfunction/ failure
1. glucose and fat metabolism * hypoglycaemia 2. defence against infection via kuppfer cells in reticuloendothelial system. * increased susceptability to infection - sponttaneous infectionmay occur 3. detoxification / metabolism * ADRs, ODs * buildup of ammonia --> hepatic encepalopathy 4. excretion * buildup of bilirubin --> jaundice: pruritus and stool + urine changes. 4. protein synthesis of albumin and clotting factors * oedema * bleeding and bruising easily 5. oestrogen regulation * gynocomastea * amenorrhoea * impotence
498
what is an acute phase protein give 2 examples
a protein that rises in response to inflammation - CRP - ferritin
499
what are the liver function tests AND how are they grouped?
1. tests that show the liver's synthetic function * albumin * prothrombin time * bilirubin 2. tests that differnetiate between cholestasis and hepatocellular damage * Alanine transaminase (ALT) * Aspartate aminotransferase (AST) * Alkaline phosphatase (ALP) * Gamma-glutamyltransferase (GGT)
500
a jaundiced pt with raised ALP + ALT indicates ...
pre-hepatic cause of jaundice such as Gilberst syndrome
501
how does ALT respond to hepatic injury
ALT is found in high concentrations within hepatocytes and enters the blood following hepatocellular injury --> a rise in ALT It is, therefore, a useful marker of hepatocellular injury.
502
what blood test is a good marker of hepatocellular injury
ALT
503
where can ALP be found
- liver - bone tissue - bile duct
504
what blood test is a good marker of cholestasis
ALP
505
how does ALP respond to cholestasis
- increases - ALP is often raised in liver pathology due to increased synthesis in response to cholestasis. - As a result, ALP is a useful indirect marker of cholestasis.
506
when is it importanat to assess GGT levels
If there is a rise in ALP, it important to review the level of gamma-glutamyl transferase (GGT).
507
a raised GGT level suggest ...
- biliary epithelial damage - bile flow obstruction. - Response to alcohol and drugs such as phenytoin. - A markedly raised ALP with a raised GGT is highly suggestive of cholestasis.
508
what are the livers main synthetic functions
* Conjugation and elimination of bilirubin * Synthesis of albumin * Synthesis of clotting factors * Gluconeogenesis
509
how does albumin respond to hepatic injury
it falls
510
what could cause a fall in albumin levels?
* Liver disease resulting in a decreased production of albumin (e.g. cirrhosis). * Inflammation triggering an acute phase response which temporarily decreases the liver’s production of albumin. * Excessive loss of albumin due to protein-losing enteropathies or nephrotic syndrome.
511
how does prothrombin time change in response to liver injury WHY?
* it increases. - the liver synthesises clotting factors. So in liver disease or dysfunction, less clotting factors are made --> longer prothrombin time
512
which pathway does prothrombin time assess
extrinsic
513
ALT/AST ratio can be used to determine...
the likely cause of liver dysfunction * ALT > AST is associated with chronic liver disease * AST > ALT is associated with cirrhosis and acute alcoholic hepatitis
514
urine and stool presentation in pre-hepatic jaundice
Normal urine + normal stools
515
urine and stool presentation in hepatic jaundice
Dark urine + normal stools
516
urine and stool presentation in post-hepatic jaundice
Dark urine + pale stools

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