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(Inflammatory Bowel Disease, Food Poisoning, Liver, Gallstones and…

- - - - Notification to Public Health to investigate outbreaks
      - Appropriate investigation and public health control measures
  - - - S. aureus, Clostridium spp, B. cereus
      - Campylobacter spp
        
        Most common cause of bacterial food poisoning in developed countries
        
        4 species associated with human disease:
        
        C. jejuni = most common
        
        C. coli (cattle, swine, birds)
        
        C. fetus
        
        C. lari (seabirds in particular)
        
        epidemiology
        
        Source
        
        Normal flora: cattle, swine, birds
        
        Zoonosis - to humans from animals/animal products: Carcasses/meat contaminated from faeces during slaughtering
        
        Route of transmission:
        
        Foodborne
        
        undercooked meat and meat products (e.g., chicken)
        
        raw or contaminated milk
        
        Contaminated water or ice
        
        Person-person spread rare
        
        Cases peak in summer months (barbecue season)
        
        Pathogenesis
        
        Ingested
        
        Adheres to jejunum and ileum
        
        Cytotoxin causes local damage (mucosal invasion)
        
        Occasionally severe haemorrhagic necrosis of the small intestine
        
        May also have large bowel involvement with crypt abscess formation in severe cases (Differential Diagnosis = Ulcerative colitis)
        
        Bloodstream spread in some people
        
        Incubation period 2-4 days, can be up to 8-9 days
        
        Clinical Features + complications
        
        Clinical:
        
        Prodromal illness (fever, headache)
        
        Diarrhoea (may be bloody)
        
        Abdominal pain – can be severe
        
        Resolves 5-7days
        
        Complications:
        
        Toxic megacolon
        
        Bacteraemia (extremes of age / immunosuppressed)
        
        Guillain-Barre syndrome (< 1 in 1000 cases)
        
        Laboratory diagnosis
      - E. coli
      - Non-typhoidal Salmonella, Shigella spp
        
        Salmonella
        
        Salmonella enterica – Overview
        
        Enterobacterales: Gram-negative bacilli
        
        Facultative anaerobes with peritrichous flagellae
        
        Typhoidal/ Enteric fever Salmonellae
        
        Serotype Typhi
        
        Chronic carriage, Definition: positive stool cultures 12 months after overcoming the disease
        
        Incidence: up to 6% become chronic carriers
        
        Potential to transmit S. typhi indefinitely
        
        Usually asymptomatic
        
        May have increased risk of gallbladder cancer
        
        Treatment: ciprofloxacin for at least 1 month
        
        Chronic carriers are not allowed to work in the food industry
        
        Serotype Paratyphi: a,b & C
        
        Paratyphoid Fever
        
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        Humans the only host
        
        Enteric fever
        
        Carrier state
        
        Enteric Fever:
        
        Pathogenesis
        
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        Epidemiology
        
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        Clinical Features
        
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        Diagnosis
        
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        Treatment
        
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        Prevention
        
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        Non-typhoidal Salmonellae
        
        Serotype Enteritidis
        
        Serotype Typhimurium
        
        Humans and animals can be hosts
        
        Zoonoses i.e., pathogens of animals, man is an incidental host
        
        Food poisoning / gastroenteritis
        
        Salmonella gastroenteritis caused by Non-typhoidal salmonellae e.g. Salmonella Enteritidis and Salmonella Typhimurium
        
        Over 2,200 different serovars
        
        Source: GIT animals & reptiles (pets) & the environment
        
        Transmission
        
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        Incubation period: 18-72 hours
        
        90% reptiles carry it - Non-typhoidal Salmonella are normal flora in reptiles such as turtles. Cases of salmonellosis in young children have been linked to pet reptiles; for this reason, reptiles are not recommended as pets for children under 5. Contact with other animals, including dogs and cats, is also associated with salmonellosis
        
        lassified according to their O (Somatic- lipopolysaccharide) and H (Flagellar) antigens using specific antisera
        
        Salmonella typhimurium, Salmonella enteritidis, Salmonella dublin
        
        Food Sources
        
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        Salmonella Gastroenteritis Pathogenesis (Non-typhoidal Salmonellae) : Ingesrion of organism --> colonization of lower intestine (ileum and cecum) --> mucousal invasion --> acute inflammation, activation of adenyl cyclase --> fluid production (large and small bowel) --> diarrhea
        
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        Clinical Features
        
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        Management
        
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        Prevention
        
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        Virulence factors
        
        Adhesion
        
        Motility
        
        Intracellular invasion
        
        Anti-phagocytic
        
        Toxin production
        
        Salmonella laboratory diagnosis: Applies to both enteric fever and non-typhoidal salmonella
        
        Direct PCR on faeces increasingly used for non-typhoidal salmonellae
        
        Non-lactose fermenter (yellow colonies) on MacConkey agar
        
        R to bile salts
        
        Black-centred colonies on XLD (xylose lysine deoxycholate) agar, due to hydrogen sulphide (H2S) production (differentiating them from Shigella spp.)
        
        Selective media eg XLD (Xylose lysine desoxycholate) agar….H2S production
      - Vibrio spp
      - Yersinia spp
    - - Cryptosporidium parvum,
      - Giardia lamblia (giardiasis),
      - Entamoeba histolytica (amoebiasis), travel-associated
      - Intestinal tapeworms
  - - - a. Toxin production in vivo e.g., e.g., B. cereus, C. perfringens
      - b. Multiplication/tissue invasion
    - - S. aureus
        
        Heat-stable enterotoxin ingested in food
        
        (dairy, produce, meats, eggs, salads)
        
        Food handler contaminates food: left at room temperature = organisms multiply + produce toxin.
        
        Person ingests enterotoxin
        
        It works fast! - 1-8 hours
        
        Vomiting predominates, occasionally diarrhoea
        
        Lasts 8-24 hours
        
        Outbreaks especially in summer
        
        Diagnosis = history
        
        Treatment = supportive
      - B. cereus(Bacillus cereus)
        
        Type 1 – Emetic Syndrome
        
        Ingestion of preformed toxin
        
        Fried rice – boiled allowed to cool slowly at room temperature/ held for long period
        
        Germination from spores with release of toxin
        
        Rapid heating does not destroy the toxin
        
        It works fast! Incubation 1-6 hours
        
        Predominantly vomiting, abdominal cramps
        
        May have diarrhoea
        
        Lasts 2-10 hours
        
        Type 2 - Diarrhoeal Syndrome
        
        Spores ingested in food: Meats, salads, chicken soup ??spices contaminated with spores
        
        Toxin production after spores germinate
        
        Incubation 6-14 hours
        
        Diarrhoea mainly, lasts 8-24h
        
        For both:
        
        Diagnosis = history
        
        Treatment = supportive
      - clostridium spp
        
        Clostridium perfringens
        
        Food contaminated with heat resistant spores ingested: Incorrectly stored cooked meat dishes, gravy, dairy products
        
        Toxin production in vivo (multiplication in the small intestine, sporulation + enterotoxin production)
        
        Incubation 8-24 hours
        
        Profuse diarrhoea, occasionally vomiting
        
        Lasts about 1-3 days
        
        Clostridium botulinum
        
        Food contaminated with toxin (neurotoxin) ingested (improperly canned/(home bottled) products)
        
        Incubation 12-36 hours
        
        Toxin absorbed from GIT into bloodstream + binds irreversibly to presynaptic nerve endings (peripheral and cranial nerves), inhibits acetylcholine release
        
        Acute descending symmetrical weakness / bilateral cranial nerve palsies
        
        Paralysis, mechanical ventilation required
        
        High mortality - 20%
        
        Treat with antitoxin
  - - - PCR
      - Selective culture for bacteria
      - Light microscopy for protozoa
- - - - a/w metabolic syndrome (type 2 DM, obesity etc.)
    - - HFE protein interacts with the transferrin receptor TFRC. Its primary mode of action is the regulation of the iron storage hormone hepcidin.
      - Wilson's disease is a rare inherited disorder that causes copper to accumulate in your liver, brain and other vital organs.
    - - Chronic (passive) venous congestion of liver
        
        a/w right heart failure (e.g. cor pulmonale, mitral stenosis), most marked in rare tricuspid incompetence, constrictive pericarditis
        
        Mild elevation of liver blood tests (ALT, AST)
      - Obstruction to venous outflow from liver (hepatic vein/IVC)
        
        Budd Chiari syndrome: condition where the hepatic veins (veins that drain the liver) are blocked or narrowed by a clot (mass of blood cells). This blockage causes blood to back up into the liver --> the liver grows larger.
      - Infarction of liver extremely unusual
      - Ischaemic injury to liver (‘ischaemic hepatitis’, ‘shock liver’)
        
        associated with (a/w) hypoperfusion, hypotension/shock/circulatory failure
        
        Marked elevation of liver blood tests (ALT, AST)
        
        Outcome depends on cause
        
        Susceptibility increased by passive venous congestion or cirrhosis
    - - Liver has reserve and regenerative capacity
      - Possible outcomes? Depends on:
        
        Degree of damage?
        
        If very extensive, risk of acute liver failure
        
        If transient and no acute liver failure, recovery
        
        If on-going/repeated insult – chronic damage
    - - If on-going insult, chronic disease (defined as >6/12)
        
        Fibrosis, increasing degrees with progression to:
        
        Cirrhosis
      - Different causes may co-exist, be superimposed, potentiate
    - - Direct cytopathic/cytotoxic/ischaemic effects
      - Damage to hepatocytes rendered antigenic (e.g. HBV)
      - Damage to cells perceived as antigenic (e.g. autoimmune hepatitis)
    - - Single cells die (apoptosis)
      - Small groups of cells die (spotty necrosis)
      - Large confluent groups of cells die (bridging necrosis)
      - Massive hepatic necrosis
  - - - Hepatic artery
      - Portal vein
    - - Smallest branches of
        
        Portal vein
        
        Hepatic artery
        
        Bile duct
      - Sharp interface between portal tract and surrounding parenchyma
    - - Bile formed by hepatocytes
      - Secreted into canaliculi between hepatocytes
      - Small ductules form from canaliculi, these then join to form small ducts in portal tracts
      - Left + right hepatic duct = Common hepatic duct
      - Common hepatic duct joined by cystic duct = Common bile duct
      - 75%: CBD + pancreatic duct join at ampulla
      - Gall bladder for bile storage only
  - - - Bilirubin: excretion
      - Bile salts: digestion - fat/fat-soluble vitamins ADEK
  - - - How much portal/periportal and/or lobular inflammation is there?
      - Interface inflammation = “piecemeal necrosis”
      - Specific pattern of portal/periportal damage
    - - Portal fibrosis
      - Periportal fibrosis (sometimes perivenular/perisinusoidal pattern in alcohol/NAFLD)
      - Bridging fibrosis: portal to portal tract or portal to central vein
      - Cirrhosis
        
        Diffuse distortion of liver architecture
        
        Fibrous bands/septa, surrounding
        
        Regenerative nodules
        
        Distorted vascular relationships
        
        Cirrhosis causes portal hypertension
        
        Functional capacity of liver reduced
        
        Risk of hepatocellular carcinoma
        
        Structural state = end-stage of chronic liver disease due to ongoing chronic damage
        
        Diminished reserve
        
        Vascular changes in liver due to cirrhosis:
        
        Obliteration/thrombosis of veins within liver
        
        Collateral channels/shunts form within liver
        
        Sinusoids become “capillarised” (lose fenestrations)
        
        Hepatic venous pressure gradient (HVPG) rises
        
        Portal hypertension in cirrhosis
        
        Initiated by increased hepatic resistance to portal blood flow, HVPG rises (structural > functional)
        
        Augmented by splanchnic vasodilatation (via. NO), increasing portal blood flow
        
        Splanchnic vasodilatation lowers TPR and BP
        
        Compensatory increase in cardiac output = hyperdynamic circulation of cirrhosis
        
        Splanchnic vasodilatation triggers compensatory mechanisms
        
        Compensation for widespread vasodilatation
        
        Activation renin-angiotensin-aldosterone system
        
        Stimulation of ADH secretion
        
        Sodium and water retention
        
        Reflex renal vasoconstriction (reducing perfusion and GFR – risk for hepatorenal syndrome [HRS])
        
        ascites
        
        Sodium and water retention in a/w portal hypertension
        
        Preferential accumulation of fluid in peritoneal cavity
        
        Leakage from peritoneal vessels
        
        Higher mean hydrostatic pressure due to portal hypertension
        
        Lower oncotic pressure to keep fluid in, due to low albumin
        
        There is an increase in blood supply to the intestines due to splanchnic vasodilation. This means if there is more blood getting to the intestines, then more blood must leave the intestines. Therefore there is more blood in the portal system flowing faster. This increases the pressure.
        All of the extra blood is going into the liver. Under normal circumstances the liver has a low resistance and blood can pass through the liver to the right side of the heart. In cirrhosis the liver is blocked. Thus there is block to the flow of blood, this increases the pressure in the portal venous system further.
        
        Portal hypertension & shunts
        
        Attempt to decompress portal hypertension leads to development of collaterals:
        
        Intrahepatic porto-systemic shunts/collaterals
        
        Extrahepatic porto-systemic anastomoses dilate
        
        Therapeutic insertion of shunt (TIPS = transjugular intrahepatic porto-systemic shunt)
        
        “Shunted” blood by-passes liver
        
        Further reduces liver function (increases risk HE)
        
        Exacerbated by ‘capillarisation’ of sinusoids
        
        Reduces perfusion of liver (worsening damage)
        
        Compensated versus decompensated cirrhosis
        
        Compensated (“silent”)
        
        May or may not have biochemical/radiological abnormality
        
        May or may not have signs of chronic liver disease/portal hypertension
        
        May or may not have varices on OGD (gastroscopy)
        
        Potentially unstable state
        
        Further injury may trigger decompensation:
        
        Infection, bleeding, hypotension, alcohol, medications, dehydration, trauma, surgery
        
        Decompensated (i.e. key complications)
        
        Ascites (may become refractory to treatment)
        
        Hepatic encephalopathy
        
        Variceal haemorrhage
        
        Hepatorenal syndrome (HRS)
        
        Jaundice
        
        Infection (esp. spontaneous bacterial peritonitis)
        
        Hepatocellular carcinoma
        
        Key effect on prognosis (rate of progression)
        
        1 year mortality compensated 1%
        
        1 year mortality compensated with varices 4%
        
        1 year mortality decompensated, ascites 20%
        
        1 year mortality decompensated, other features >50
        
        Changing concepts of cirrhosis
        
        old
        
        Single terminal disease state
        
        Aetiology not that important
        
        Implication that progression inevitable
        
        Defined as a diffuse state
        
        Ignored fact that changes can be patchy, with different stages of evolution to cirrhosis in different parts of liver
        
        Biopsy diagnosis prone to major sampling error
        
        But recognition that prognosis varies widely (depends on decompensation)
        
        Fixed, irreversible, static state always?
        
        Now: recognized as possibly dynamic state
        
        Stop or reverse fibrosis?
        
        Originally an autopsy diagnosis
        
        new
        
        Progression may be modified
        
        Treatment can induce regression of structural changes
        
        Fibrosis is a dynamic (not an entirely fixed) process
        
        Key importance of aetiology
        
        Active management
        
        Early diagnosis, limit progression, avoid complications
        
        “Advanced stage of chronic liver disease”
        
        To include advanced fibrosis and replace “cirrhosis”?
        
        Only becomes inevitable “end stage” when HVPG reaches critical threshold (= decompensation)
        
        Clinical approach to cirrhosis
        
        Prevent/slow/reverse progression of liver disease & development of decompensation
        
        Specific tx/risk modification for underlying disease
        
        Avoid further or additional insults to liver
        
        Screen/treat varices and screen for HCC
        
        UK NICE guidelines (2016)
        
        Actively screen for advanced fibrosis
        
        HCV
        
        Heavy alcohol intake (sustained >50u/wk M, >35u/wk F)
        
        NAFLD (Nonalcoholic fatty liver disease (NAFLD) is an umbrella term for a range of liver conditions affecting people who drink little to no alcohol. As the name implies, the main characteristic of NAFLD is too much fat stored in liver cells.) with positive ELF blood test
        
        Prevent, identify and treat promptly decompensation events
        
        Prevent/reduce risk of recurrent or additional events
        
        Listing for transplantation – if and when?
        
        Future – anti-fibrotic?
        
        Considerations in chronic liver disease:
        
        Medications: dose adjustment or avoidance
        
        Risk of surgery: infection, bleeding, healing, ascites
        
        No significant generalized bleeding tendency
    - - Silent or mild non-specific symptoms or at-risk history
        
        Identified by liver blood tests
        
        Identified by imaging
      - Symptoms/signs possible liver disease (e.g. jaundice)
        
        Acute liver disease (short of acute liver failure)
        
        Acute flare or exacerbation of a chronic disease
        
        End stage of chronic disease (cirrhosis)
      - Acute liver failure
      - Decompensation of cirrhosis
        
        i.e. major complications of cirrhosis
- - - - Post acute cholecystitis…….mucocoele (is mucous cyst. Mucocoele form when mucus or saliva escapes into surrounding tissues and a lining of granulation or connective tissue is formed to create a smooth, soft round fluid-filled lump. They most commonly occur on the inner surface of the lower lip (75% of cases) but may also appear on the floor of the mouth (in this region they are known as ranulae) or on the gingiva (gums), buccal mucosa (inner lining of the cheeks) and tongue), empyema, gangrene, perforation
      - Acute Cholecystitis
        
        Analgesia
        
        Abdominal US
        
        IV antibiotics?? Initially a chemical sterile inflammation
        
        IV fluids
        
        Nil Po if vomitting
        
        Laparoscopic Cholecystectomy (early V late)
      - Mirizzi’s Syndrome (stone in Hartman’s pouch causing obstructive jaundice). Hartmann's pouch is a diverticulum that can occur at the neck of the gall bladder.
      - Gallbladder carcinoma (porcelain gallbladder)
      - Chronic Cholecystitis
    - - Biliary colic
        
        Analgesia
        
        IV fluids
        
        US abdomen
        
        Laparoscopic Cholecystectomy
      - Intense pain (RUQ or epigastric)
      - Distinct attacks
      - Intense
      - Usually within hours of eating meal
      - Few abdominal signs
    - - “Gallstone Ileus”
      - The least common!
      - Fistula between gallbladder and duodenum
      - Elderly women
      - Presents as sub-acute small bowel obstruction
- - - - Non-neoplastic lesions can mimic neoplasms
      - Cysts, haemangiomas, regenerative tumour-like lesions, abscesses: US, CT, MR + context diagnostic
    - - Primary Liver Tumours
        
        Benign
        
        Hepatic adenoma (= liver cell adenoma, anabolic steroids, (OCP))
        
        Bile duct adenoma (rare)
        
        Haemangioma
        
        Malignant
        
        Hepatocellular carcinoma (=liver cell carcinoma, hepatoma, HCC)
        
        Europe/North America relatively uncommon
        
        East and SE Asia/Africa common
        
        Associated with cirrhosis/chronic hepatitis (>90%)
        
        Can occur in non-cirrhotic fibrotic HBV livers
        
        Single mass or multifocal, may have vascular invasion
        
        Metastases not as usual as in some other tumour types
        
        Presentation
        
        High incidence areas - co-presents with or precedes cirrhosis, in relatively young patients
        
        Low incidence areas - decompensation of cirrhosis, 3% HCC/yr, vague/changing symptoms
        
        Diagnosis
        
        Radiology: US, specific contrast-enhanced CT and/or MRI protocols
        
        Assessment of nodules in cirrhosis, >1cm or enlarging
        
        Alpha-fetoprotein (AFP): ‘tumour marker’
        
        Biopsy rarely necessary
        
        Screening
        
        High risk patients (compensated cirrhosis), every 6/12
        
        US
        
        AFP blood test – alone not specific/sensitive enough
        
        Prevention
        
        Treatment of cause of underlying chronic liver disease?
        
        Prevention of chronic liver disease (HBV vaccination)
        
        Treatment
        
        Resection if early
        
        OLT
        
        Local ablative treatments: radiofrequency, arterial chemo- embolization
        
        Prognosis – depends on:
        
        Stage
        
        Degree of liver function impairment
        
        Co-morbidity
        
        Typically poor but in selected cases 5 year survival of 50%
        
        Aetiology
        
        Cirrhosis (HBV/HCV/HFE > other causes cirrhosis?)
        
        Chronic HBV directly oncogenic?
        
        Aflatoxins - fungal contaminants of food stores
        
        Intrahepatic cholangiocarcinoma (=intrahepatic bile duct adenocarcinoma)
        
        Cholangiocarcinoma
        
        Adenocarcinoma arising from bile duct epithelium: Intrahepatic or extrahepatic location
        
        Commonest site at hilum of liver : Klatskin tumour = obstructing bifurcation of CHD
        
        Intrahepatic cholangiocarcinoma a minority of primary liver malignancy (10%)
        
        Associations: PSC Primary sclerosing cholangiti. In primary sclerosing cholangitis, inflammation causes scars within the bile ducts. These scars make the ducts hard and narrow and gradually cause serious liver damage.
        
        Rare: chronic fluke infestation, congenital biliary abnormalities
        
        Diagnosis difficult and often late, outcome poor
        
        Selected cases – surgical resection
        
        Typically, palliate obstruction with stent placement
        
        Haemangiosarcoma (textbook rarity)
      - Secondary Tumours/Liver Metastases
        
        Commonest ‘liver tumour’ in Europe/N America
        
        Carcinoma - primary in GI tract, lung, breast
        
        Other malignancies can infiltrate liver e.g. lymphoma, leukaemia
        
        Metastases may obstruct bile flow
        
        Early: few symptoms/effects, Alk Phos raised
        
        Late: rising bilirubin, jaundice
        
        Generally poor prognosis
        
        Identify primary site of origin - treatment
        
        Surgery for isolated colorectal metastases
        
        Immunohistochemistry is used in liver metastasis histology
        
        CK20, CDX2 - Large intestine
        
        TTF1 - Lung
        
        S100, Melan A, HMB, SOX10- Melanoma
        
        Gross Appearance of Metastases (secondaries) to Liver:
        Multiple pale deposits are metastases
        (don’t confuse with cirrhosis, not diffuse change
  - - - Exocrine composed of glandular acini grouped into lobules
      - Exocrine secretions drain via ducts, joining to form pancreatic duct
    - - Small pancreatic duct (centre) surrounded by exocrine pancreatic glandular acini.
      - Pale collection of cells (left centre) is islet of Langerhans
    - - Exocrine
        
        Malignant: pancreatic (ductal) adenocarcinoma
        
        Other less common tumours, sometimes cystic
        
        May be benign or have intermediate behaviour
        
        Some recognised as precursors to pancreatic ca
      - Endocrine
        
        Pancreatic neuroendocrine tumours rare
        
        Behaviour difficult to predict
        
        Classified by hormone type produced
        
        Hormone may cause clinical symptoms
        
        Association with parathyroid hyperplasia and pituitary adenomas in inherited MEN type 1 syndrome
        
        Multiple endocrine neoplasia, type 1 (MEN 1), sometimes called Wermer's syndrome, is a rare disorder that causes tumors in the endocrine glands and parts of the small intestine and stomach
      - Pancreatic Carcinoma
        
        Adenocarcinoma, arising from pancreatic ducts
        
        Common: 5th/6th by rank of cancer deaths
        
        M>F, 80% >60 years
        
        60-70% from head, rest from body & tail
        
        Spread
        
        Direct local: peritoneum (vessels, nerves), duodenum, CBD = ‘locally advanced’
        
        Lymph nodes or to liver (50% metastatic at diagnosis)
        
        Risk factors (relatively weak): Smoking, DM, chronic pancreatitis, Family history (5%)
        
        Symptoms
        
        Typically symptomatic only with advanced disease
        
        Easily missed
        
        Anorexia, weight loss
        
        Painless obstructive jaundice (tumours in head)
        
        Vague abdominal pain, may radiate to back
        
        Rare: palpable mass, thrombotic tendency --> Migratory thrombophlebitis = Trousseau’s sign
        
        Diagnosis
        
        CA 19-9 serum marker for pancreatico-biliary cancer: Not useful in diagnosis, used for response/relapse assessment
        
        Imaging (US, CT, EUS), FNA cytology via EUS
        
        Avoid unnecessary invasive investigation in majority
        
        Prognosis
        
        5 year survival <3%, most patients die <1 year
        
        10-20% suitable for surgery
        
        10-20% 5yr survival in these selected patients
        
        Treatment
        
        Pancreatico-duodenectomy (Whipple’s procedure)
        
        Chemotherapy (adjuvant), modest benefit
        
        Majority: palliation
        
        Stenting, analgesia
        
        Painless extrahepatic cholestasis/obstructive jaundice a/w weight loss: suspect pancreatico-biliary malignancy
    - - Chronic Pancreatitis
        
        Pancreatic function impaired (exocrine>endocrine)
        
        Distortion of ductal system: Strictures, dilatation and cysts behind strictures, pancreatic ductal stones
        
        Causes:
        
        Alcohol
        
        Idiopathic
        
        Childhood causes including cystic fibrosis
        
        CF more typically a/w pancreatic insufficiency due to damage but without clinical ‘chronic pancreatitis’
        
        Symptoms:
        
        Pain (dull, epigastric, radiating to back)
        
        Weight loss
        
        Steatorrhoea and malabsorption
        
        Secondary diabetes mellitus
        
        Treatment: Analgesia (opiates), enzyme supplements
        
        Diagnosis:
        
        Difficult, sometimes diagnosis of exclusion
        
        Amylase not useful
        
        Tests of pancreatic function not routine
        
        Imaging in advanced disease
        
        Patchy, irreversible fibrosis, ongoing inflammation
      - Acute Pancreatitis
        
        Definition: Acute inflammation of the pancreas due to injury.- Associated release of inflammatory cytokines and pancreatic enzymes.
        
        Occurs at any age
        
        Overall mortality 10%
        
        Accounts for 3% hospital admissions with abdominal pain
        
        Acute Pancreatitis Symptoms
        
        Nausea and vomiting
        
        Pain
        
        Often sudden in onset
        
        Radiates to back
        
        Relieved by sitting forward
      - Causes of pancreatic injury
        
        “I GET SMASHED”
        
        Idiopathic
        
        Gallstones
        
        EtOH (Alcohol)
        
        Trauma
        
        Steroids
        
        Mumps
        
        Autoimmune
        
        Scorpion sting
        
        Hypertriglyceridaemia/Hypercalcaemia
        
        ERCP
        
        Drugs (eg Thiazides)
        
        80% is caused by Gallstones, EtOH (Alcohol), Trauma
      - Pathogenesis: Autodigestive process
        
        Activation of pancreatic enzymes secondary to injury.
        
        Pancreatic enzymes (eg lipase, trypsin) act on pancreatic tissue.
        
        Local and systemic inflammatory response.
      - SIGNS: DEPEND ON SEVERITY
        
        Dehydration
        
        Epigastric guarding
        
        Tachycardia, tachypnoea, mild pyrexia/
        
        If cholangitis (bile duct inflammation due to gallstones)
        
        Icterus: yellowish pigmentation of the skin, tissues, and body fluids caused by the deposition of bile pigments : jaundice
        
        Pyrexia
        
        RUQ pain
        
        Seen in haemorrhagic pancreatitis
        
        Cullen’s sign (Peri-umbilical bruising)
        
        Grey Turner’s sign (Flank Bruising)
      - Classification: Atlanta Classification (Revised 2008)
        
        Mild: No organ failure, No local or systemic complications.
        
        Moderate: Transient organ failure (<48hrs). Local or systemic complications.
        
        Severe: Persistent organ failure (>48hrs).
      - Differential diagnosis
        
        Gastritis
        
        Cholecystitis
        
        Perforated PUD
        
        Hepatitis
        
        Pneumonia
        
        MI
        
        Appendicitis
      - Prognostic Scores
        
        Severity stratification
        
        Glasgow (IMRIE) Criteria
        
        P – Pao2 <8kPa (arterial sample)
        
        A – Age >55
        
        N – Neutrophilia (WCC >15x10^9/L)
        
        C – Calcium <2mmol/L
        
        R – Renal function (urea >16mmol/L)
        
        E – Enzymes (LDH >600iu/L, AST > 200iu/L)
        
        A – Albumin (32g/L)
        
        S – Sugar (blood glucose >10mmol/L)
        
        Score greater than 3 predicts severe disease → High dependency/ICU care with hourly monitoring of vital signs
        
        Ranson Criteria
        
        0 hours
        
        Age >55
        
        White blood cell count > 16x10^9/L
        
        Blood glucose > 11.1 mmol/L (200 mg/dL)
        
        LDH >350 U/L
        
        AST >250 U/L
        
        48 hours
        
        Hematocrit Fall by ≥10 percent
        
        Blood urea nitrogen Increase by ≥5 mg/dL (1.8 mmol/L) despite fluids
        
        Serum calcium <8 mg/dL (2 mmol/L)
        
        pO2 <60 mmHg
        
        Base deficit >4 MEq/L
        
        Fluid sequestation >6000 mL
        
        The presence of 1 to 3 criteria represents mild pancreatitis;
        the mortality rate rises significantly with four or more criteria.
      - Severity/Grading score
        
        Balthazar ct score
        
        A: normal pancreas
        
        B: enlargement of pancreas
        
        C: inflammatory changes in pancreas and peripancreatic fat
        
        D: ill-defined single peripancreatic fluid collection
        
        E: two or more poorly defined peripancreatic fluid collections
        
        Pancreatic necrosis
        
        None: 0
        
        ≤30%: 2
        
        30-50%: 4
        
        50%: 6
        
        Max score obtained 10
        
        Score
        
        0-3: mild acute pancreatitis
        
        4-6: moderate acute pancreatitis
        
        7-10: severe acute pancreatitis
      - Investigations
        
        Bloods (FBC, CRP, LFT’ s, U&E, Calcium, Albumin, glucose)
        
        ABG
        
        CXR (Look for free air under diaphragm)
        
        Ultrasound Abdomen (don’t forget to look for gallstones!!)
        
        CT pancreas protocol (to judge severity/complications)
    - - Collection of pancreatic fluid in disrupted tissue in or adjacent to pancreas
      - Defined wall but not a true cyst (no epithelial lining)
      - Causes: acute or chronic pancreatitis, pancreatic surgery or trauma
      - Complications: pain/pressure, infection, erosion with fistula or blood vessel damage
      - Aspirate or drain by endoscopy or surgery
  - - - Bile salts and phospholipids (detergent action for digestion of fats)
      - Excretory: bilirubin, cholesterol, calcium salts, copper
    - - Common, easily identified with ultrasound
      - Formed from bile constituents (+/- calcium)
        
        Predominantly cholesterol >90%, may be mixed
        
        Predominantly bilirubin <10%
        
        10% only are radio-opaque (+ calcium) on plain x ray
      - Cholelithiasis = stones in gall bladder
      - Choledocholithiasis = stones in common bile duct
        
        Typically, pass from gall bladder to CBD via cystic duct
        
        Less commonly, form primarily in CBD (common bile duct)
      - Significant part of workload for general surgeons
      - Who Gets Gallstones? Predisposing factors:
        
        Female (16% of US women vs 9% US men)
        
        Increasing age
        
        Obesity, high fat/low fibre
        
        High lipids, type 2 DM
        
        Geography and race (Native Americans, Hispanic)
        
        High does oestrogen: pregnancy, ?Pill, ?HRT
        
        Gall bladder hypomotility/stasis: rapid weight loss (bariatric surgery), fasting, TPN. Total parenteral nutrition (TPN) is a method of feeding that bypasses the gastrointestinal tract. Fluids are given into a vein to provide most of the nutrients the body needs.
        
        Bilirubin (pigment) stones: bile salt depletion (Crohn’s ileitis, ileal surgery), cirrhosis, haemolysis, parasites
      - Pathogenesis:
        
        Altered bile composition (“lithogenic bile”), precise mechanism typically unexplained (cholesterol supersaturation?)
        
        Gall bladder hypomotility
        
        Phases of accelerated nucleation and growth (sluggish/static gall bladder) in stone formation
        
        Stones form in sequential episodes over long period
        
        Lithogenic bile may cause microlithiasis and bile sludge, as well as or instead of stones
        
        Infection not a primary event in pathogenesis of stones
      - Symptomic vs Asymptomatic GallStones
        
        Symptomatic GallStones & Biliary Colic
        
        Pain will recur in 70%
        
        1-2% with biliary colic get complications of gallstones
        
        Steady RUQ/epigastric pain, >30 minutes, <4 hours
        
        May radiate to back, right shoulder
        
        Usually crescendo pattern/persistent
        
        Visceral pain due to distension of GB following transient obstruction of cystic duct
        
        No fever/raised WCC/tenderness
        
        Moderately severe pain: differential diagnosis – dyspepsia, PUD (Peptic ulcer disease), acute pancreatitis, oesophageal pain, MI
        
        Biliary colic most common symptom related to gall stones – may be difficult to confidently diagnose
        
        Asymptomatic GallStones
        
        Most gallstones asymptomatic/incidental findings
        
        Only 20% cause symptoms if followed up x 15yrs
        
        Biliary pain (biliary colic) develops in 1-4% annually
        
        If asymptomatic, treatment not indicated
        
        Other symptoms – vague abdominal pain, dyspepsia, fatty food intolerance – are they due to gallstones?
        
        Distinction between asymptomatic and symptomatic can be difficult
        
        Will patients benefit from cholecystectomy?
      - Complications of GallStones
        
        Acute cholecystitis and its complications
        
        Nearly always (>90%) a/w gallstones
        
        Cystic duct obstruction (sustained), causing:
        
        Stasis in gall bladder
        
        Secondary infection
        
        Small % acalculous (i.e. without stone)
        
        Fever, nausea, vomiting, pain RUQ x days
        
        RUQ tenderness, Murphy’s sign +ve
        
        High WCC, US findings characteristic
        
        No jaundice (exception: rare Mirizzi syndrome)
        
        Fluid, analgesia, antibiotics
        
        Cholecystectomy
        
        Complications of Acute Cholecystitis
        
        Occur in 10-20%
        
        Empyema (chronically obstructed, ongoing active inflammation)
        
        Mucocoele (chronically obstructed, sterile)
        
        Necrotising inflammation with risk of perforation
        
        Pericholecystic abscess or generalised biliary peritonitis (very rare, high mortality)
        
        Adhesions to duodenum with cholecysto-duodenal fistula
        
        Fistula followed by risk of gallstone ileus (small intestinal obstruction due to stone)
        
        Common bile duct obstruction if stone moves into CBD (or forms there)
        
        Obstructive jaundice (extrahepatic cholestasis)
        
        Ascending (acute) cholangitis
        
        Infection in static, obstructed bile
        
        High fever, pain, jaundice = Charcot’s triad
        
        Add hypotension, altered mental state = Reynolds’ pentad
        
        Requires urgent decompression
        
        Acute pancreatitis
        
        Acute inflammation of pancreas
        
        10-20/million, mortality ?5% (higher if severe)
        
        Single or recurrent attacks
        
        Pathogenesis
        
        Premature (intra-pancreatic) activation of pancreatic enzymes
        
        Once initiated, irreversible cascade (auto-digestion)
        
        May trigger systemic inflammatory response syndrome (SIRS) if severe
        
        Obstructing stone at lower end CBD causes reflux of bile/concentration of pancreatic juices
        
        Alcohol direct toxic effect
        
        Severity of Acute Pancreatitis
        
        Mild acute pancreatitis (80% cases): Self limiting disease. Interstitial oedematous acute pancreatitis on imaging, non-necrotizing
        
        Severe acute pancreatitis (20% cases): Necrotizing inflammation of pancreas and surrounding tissue (peri-pancreatic fat)
        
        Effects of Severe Acute Pancreatitis
        
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        Causes of Acute Pancreatitis
        
        Gallstones (F>M)
        
        Alcohol (M>F)
        
        Post-ERCP (5%)
        
        Idiopathic (10%) - biliary microlithiasis
        
        Miscellaneous uncommon causes (5%)
        
        Trauma, ischaemia, major surgery
        
        Drugs, viral
        
        Hypercalcaemia, hyperlipidaemia
        
        Hereditary pancreatitis
        
        Diagnosis of Acute Pancreatitis
        
        Symptoms
        
        Epigastric pain, may radiate into back
        
        ‘Acute abdomen’, seen by surgeons
        
        If severe: differential diagnosis - MI, ruptured AAA, perforated or ischaemic abdominal organ
        
        Blood tests
        
        Blood amylase higher than 3X normal
        
        Amylase short half life
        
        Lipase used in future?
        
        If equivocal, ?radiology
        
        Try and identify cause, avoid immediate laparotomy
        
        Gall bladder adenocarcinoma (rare, low overall risk)
        
        Complications: approx. 1% risk if gallstones, higher if biliary colic
        
        Cholecystitis is an inflammation of the gallbladder wall, usually caused by obstruction of the bile ducts by gallstones, and cholangitis is inflammation of the bile ducts
      - Common Bile Duct Obstruction a/w Gallstones: Stones move to or form in CBD, may cause
        
        Obstructive jaundice
        
        Colicky pain (intermittent), elevated Alk Phos/GGT, dilated ducts (US), risk of infection
        
        Ascending cholangitis
        
        Obstruction with secondary infection
        
        Acute pancreatitis
      - Chronic Cholecystitis
        
        Histopathological finding rather than clinical entity
        
        Pathological description of findings in most gall bladders removed at surgery
        
        Always associated with gallstones
        
        No specific/reliable correlation with symptoms
        
        Gall bladder shows chronic response to repeated obstruction/inflammation
        
        Fibrotic, shrunken gall bladder with stones
        
        Thickened muscle, atrophied mucosa, diverticula
      - Gall Bladder Adenocarcinoma
        
        <1% of those with gallstones
        
        80% of cases a/w are long standing gallstones
        
        (Gallstones very common, gall bladder adenocarcinoma rare)
        
        F>M, older age group
        
        Presents late, vague symptoms, outlook poor
        
        Clinical problem: gall bladder “polyps” often identified at US
        
        Clinical problem: gall bladder “polyps” often identified at US
        
        Question is: could they be neoplasms of the gall bladder (adenomas or carcinomas)?
        
        If small/non-progressive, likely to be harmless non-neoplastic cholesterol “polyps”
  - - - Tumour
        
        Adenocarcinoma of pancreas
        
        Extra-hepatic bile duct adenocarcinoma
      - Benign stricture (post-operative or PSC)
      - Mass outside CBD/CHD compressing duct
        
        Mirizzi syndrome (external compression from stone in neck/cystic duct of GB)
        
        Primary tumour or metastases in lymph nodes
      - Gallstones in common bile duct
    - - US shows dilated ducts above obstruction
      - Cause may need investigation by MRCP or EUS
      - May perform ERCP for diagnosis if treatment also considered
    - - Stones
      - ERCP (Endoscopic retrograde cholangiopancreatography) with sphincterotomy +/- stone removal
      - CBD exploration at surgery (laparoscopic or open)
- - - - Autoimmune hepatitis (AIH), Wilson’s disease
    - - Proportion of HBV depending on age, most HCV, very rare HEV
    - - Alcohol-related liver disease
      - Non-alcoholic fatty liver disease (a/w metabolic syndrome)
      - Chronic inflammatory biliary tract diseases (PBC, PSC)
      - Hereditary haemochromatosis (HFE, paradoxically leads to chronic damage but without inflammation)
    - - Acute diffuse liver damage with inflammation
        
        Short of acute liver failure
        
        Viruses (esp. hepatotropic viruses HAV, HBV, HCV, HEV but also EBV, CMV, rubella)
        
        Drugs (may be identical to virus)
        
        <6/12 duration
      - Mimics:
        
        Flares/exacerbations of chronic hepatitis
        
        Alcohol-related liver disease or acute biliary obstruction may be “acute” in presentation but have distinctive features
    - - Often silent (in children > adults)
      - May be vague symptoms: nausea, anorexia, malaise
      - Very rare: acute liver failure
  - - - Screen or vague/non-specific symptoms (“fishing” with tests)
      - Known possible risk factors
      - Clinically obvious presentation
    - - “Liver profile” = ALT, AST, Alk Phos, GGT, bilirubin, albumin
      - Related to liver cell (hepatocellular) damage: Transaminases (ALT, AST)
        
        Alanine transaminase (obsolete ‘SGPT’)
        
        Aspartate transaminase (obsolete ‘SGOT’)
        
        Both leak from damaged hepatocytes
        
        ALT sensitive/specific marker for hepatocellular damage
        
        AST less specific, also in muscle, myocardium, kidney
        
        Level of rise poor correlation with severity/prognosis
        
        Very high in acute hepatocellular damage
        
        May be only mildly elevated or normal despite chronic liver disease
        
        AST/ALT ratio can be informative
        
        Usually <1, if >2 suggests alcohol-related damage
      - Related to obstruction to bile flow (cholestasis): Obstructive (Cholestatic) Liver Enzymes
        
        Alkaline phosphatase, GGT
        
        Alkaline phosphatase
        
        Situated on hepatocyte border of bile canaliculi
        
        Hepatocytes react to obstruction to bile flow with Alk Phos leak
        
        Other sources: bone, placenta
        
        Gamma-glutamyl transferase (GGT)
        
        Obstruction to bile flow, therefore:
        
        Good for correlating with elevated alkaline phosphatase to demonstrate that Alk Phos is of liver origin
        
        Also induced by alcohol, drugs
        
        Very sensitive but not specific at all
        
        Isolated rise not usually investigated
        
        Bilirubin
        
        Bilirubin, Jaundice & Cholestasis
        
        Bilirubin normal <18umol/l
        
        Jaundice = icterus, yellow discolouration of tissues (skin and sclera)
        
        Clinical jaundice = bilirubin >50umol/l
        
        “Biochemical jaundice” >18<50umol/l = hyperbilirubinaemia without jaundice
        
        Cholestasis = failure of normal bile flow, stasis of bile
        
        Jaundice variety of causes, not just cholestasis
        
        Cholestasis has other features apart from jaundice
        
        Effects of cholestasis
        
        Conjugated hyperbilirubinaemia- Jaundice, dark urine (bilirubinuria, often appears first)
        
        Obstruction to bile flow into gut- May get pale stools
        
        If chronic obstruction to bile salt excretion into gut
        
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        Elevated alkaline phosphatase/GGT
        
        Imaging critical – dilated ducts? If yes, cause?
        
        Bilirubin Metabolism
        
        Haem breakdown produces bilirubin
        
        Unconjugated bilirubin initially
        
        Highly water-insoluble, circulates bound to albumin
        
        Unconjugated bilirubin actively taken up by hepatocyte
        
        Liver cell conjugates bilirubin with glucuronate
        
        Conjugated bilirubin water soluble, can be excreted in bile
        
        Conjugation usually efficient (UDPGT-1 enzyme)
        
        Conjugated hyperbilirubinaemia causes bilirubinuria
        
        Bilirubin oxidised in bowel to urobilinogen (= faecal colour)
        
        Only paediatric labs measure unconjugated (direct) bilirubin and conjugated (indirect) bilirubin separately
      - Related to liver function
        
        Bilirubin – abnormality not liver or biliary tract specific
        
        Albumin – may reflect chronic damage
        
        Long half life
        
        Low albumin therefore reflects chronic injury to liver
        
        Very non-specific but useful in context
        
        Coagulation function (PT/INR) – acute damage
        
        Clotting factors short half life
        
        Rise correlates with degree of acute damage to liver
        
        PT sent in coagulation tube to haematology lab
      - Viral serology- A, B, C – sometimes EBV, CMV, E
      - Iron storage status- Transferrin saturation / % sat. of total iron binding capacity, Ferritin
      - Immunological injury/reaction (autoimmune)
        
        Auto-antibodies (ANA, SMA, anti-LKM, AMA, ANCA)
        
        Immunoglobulin G and M levels
      - Copper metabolism (Wilson’s disease, very rare)- Caeruloplasmin
      - Alpha-1-antitrypsin levels (A1AT def., very rare)
      - Interpretation of liver blood tests
        
        If liver blood tests are abnormal
        
        Clinical context – reason, history, examination
        
        Single test abnormal or several?
        
        Magnitude of abnormality or abnormalities
        
        Tests within normal range doesn’t exclude clinical disease
        
        Remember non-liver/biliary tract causes
        
        Pattern of abnormality, if several? Key part of analysis
        
        Hepatocellular damage (transaminases predominate)
    - - Ultrasound
        
        Dilated ducts, gallstones, focal liver lesions
        
        Liver texture (echogenicity) and border (inhomogeneity)
        
        Not sensitive for cirrhosis or mild degrees of fatty change
      - MRCP (magnetic resonance choledochopancreatography)
      - CT and/or MR (each +/- contrast enhancement)
      - Endoscopic ultrasound (EUS)
      - ERCP (endoscopic retrograde choledochopancreatography)- Diagnostic with therapeutic intent in addition (treatment of CBD stone, drain biliary tract, stent obstruction)
      - PTC (percutaneous transhepatic cholangiography)- Decompression/visualisation of obstructed biliary system
    - - Indications:
        
        Diffuse liver disease
        
        Diagnosis of cause
        
        Grade necroinflammatory activity and stage (fibrosis)
        
        Sampling variability is an issue for diffuse disease
        
        Focal liver lesion
        
        Cyst vs haemangioma vs tumour-like lesion vs tumour (benign, malignant, primary or secondary)
        
        US, CT, MR + context usually diagnostic of most lesions
      - Approaches:
        
        Percutaneous - radiological guidance, needle core of tissue
        
        Transjugular – if coagulopathy
        
        Laparoscopic – focal lesion
      - Risks: pain, bleed, bile leak, trauma
        
        2-3% hospitalised, 1/10000 mortality
        
        C/I: clotting problems, anti-clotting drugs, biliary obstruction
        
        Do: platelet count/coag screen, group and screen blood
      - Balance risks of biopsy versus benefit
        Will it affect management (prognosis, therapy)?
        Biopsy performed with diminishing frequency
      - Standard handling in laboratory:
        H&E plus routine “special” stains for fibrosis and iron + Immunohistochemistry for tumours
    - - Serum markers
        
        APRI (AST to prothrombin ratio index), NALFD fibrosis score
        
        Proprietary (e.g. Fibro Test, Enhanced Fibrosis Score [EFS])
      - Transient elastography
        
        FibroScan
        
        Liver stiffness: ultrasound assessment of velocity of elastic shear wave signal
        
        Best at identifying ends of spectrum
  - - - Acute liver failure is defined as acute liver injury with encephalopathy and deranged coagulation (INR >1.5) in a patient with a previously normal liver
      - Acute liver failure is a rare but often life threatening syndrome that is due to hepatitis from many causes
      - The causes vary throughout the world. Most involve viral hepatitis but paracetamol overdose is common in UK
      - Histologically there is necrosis of acini involving a substantial part of the liver
      - Severe fatty change may be seen in pregnancy, Reye syndrome or intravenous tetracycline
      - Some Causes of acute hepatic failure
        
        Virus - hepatitis A, hepatitis B, cytomegalovirus, haemorrhage fever virus
        
        Drug - there are many, paracetamol, antibiotics, antidepressants, salicylate (Reye syndrome), NASID’s, herbal medicines
        
        Toxins, organic solvents, mushroom toxin
        
        Hepatic failure in pregnancy - acute fatty liver of pregnancy, HELLP syndrome. HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome is a life-threatening pregnancy complication usually considered to be a variant of preeclampsia. Both conditions usually occur during the later stages of pregnancy, or soon after childbirth + can be difficult to diagnose, because all of the typical signs of preeclampsia may not be apparent, such as high blood pressure and protein in the urine. Its symptoms are sometimes mistaken for gastritis, flu, acute hepatitis, acute fatty liver disease, gall bladder disease, or other conditions.
        
        Vascular causes – Budd-Chiari syndrome, portal vein thrombosis
        
        Alpha-1 antitrypsin deficiency, Reye syndrome, Wilson’s disease
        
        Malignancies – secondary extensive metastases and infiltration
        
        Heatstroke
      - Clinical features of acute liver failure
        
        Jaundice
        
        Classification of Jaundice
        
        Mechanism/clinical context
        
        Excess production of bilirubin
        
        Abnormalities in uptake/conjugation/excretion enzymes
        
        Hepatocellular disease
        
        Cholestasis/obstruction
        
        Infiltrative diseases in liver
        
        Intrahepatic biliary tract disease
        
        Extrahepatic biliary tract obstruction/disease
        
        Site- Pre-hepatic – Hepatic - Post-hepatic
        
        Biochemical - Unconjugated (indirect) versus conjugated (direct)
        
        Causes of Jaundice
        
        Isolated hyperbilirubinaemia – consider separately
        
        Unconjugated almost always +/- sometimes jaundice
        
        Haemolysis
        
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        Gilbert’s syndrome (typically mild elevation)
        
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        Jaundice a/w liver and biliary tract disease
        
        Predominantly conjugated, a/w other abnormal liver blood tests
        
        Not useful in distinguishing hepatocellular damage and obstruction/cholestasis or acute from chronic
        
        What is the context? Pattern of other liver blood tests?
        
        Acute damage
        
        Acute obstruction/cholestasis
        
        Acute liver failure (+ HE)
        
        Acute flares of chronic disease- e.g. alcoholic hepatitis, reactivation of chronic HBV, autoimmune hepatitis
        
        Hepatic encephalopathy
        
        Spectrum of neuro-psychiatric abnormalities seen in a/w liver dysfunction and/or porto-systemic shunting
        
        Functional disturbance of brain, potentially reversible
        
        If severe a/w cerebral oedema and cerebral hypoperfusion
        
        Classification:
        
        Type A: acute liver failure
        
        Type B: porto-systemic shunting with normal liver
        
        Type C: cirrhosis (= decompensation)
        
        Episodic (may be recurrent) HE +/- persistent HE
        
        Episodic HE may be precipitated or not
        
        Spectrum of effects: on consciousness, behaviour, intellectual function, neuromuscular function
        
        Why does it happen?
        
        Reduced detoxification (endogenous and exogenous, including from gut) due to reduced liver function
        
        Unprocessed portal blood shunted through/past liver
        
        Pathogenesis - no definite single cause
        
        Ammonia accumulation (nitrogenous compounds)
        
        Altered neurotransmission (GABA, glutamate), glial fxn
        
        Precipitants in known cirrhosis:
        
        Infection
        
        Bleeding, other causes of hypoperfusion
        
        Dehydration (diuretics, paracentesis, V & D). Paracentesis is a procedure that removes fluid (peritoneal fluid) from the abdomen through a slender needle. The collected fluid is then sent to a lab for analysis to determine what is causing the excess fluid.
        
        Drugs (sedatives – opiates, benzos) or alcohol
        
        Constipation
        
        Need for TIPS or surgical shunt
        
        Treatment:
        
        Identify and correct precipitating factors
        
        Reduce ammonia production in enema, empty bowel of nitrogenous substances
        
        Lactulose
        
        Non-absorbable antibiotic (rifaximin)
        
        Fluids
        
        Stop diuretic therapy
        
        Fever, vomiting, low blood pressure, low blood glucose
        
        Cerebral oedema in 80% of patients
        
        Impaired gluconeogenesis
        
        Kidney injury – hepatorenal syndrome
        
        Renal impairment secondary to liver disease
        
        Haemodynamic effects of portal hypertension reduce renal perfusion, typically a/w ascites
        
        Diagnosis of exclusion – no other kidney pathology:
        
        Hypovolaemia/shock (e.g. infection, bleeding)
        
        Acute tubular necrosis (shock or nephrotoxic drugs)
        
        Poor prognosis
        
        Acute tubular necrosis
    - - Classified by level/site of origin of portal hypertension
      - Commonest cause is cirrhosis
      - Pathogenesis in cirrhosis:
        
        Initiated: increased resistance to portal blood flow
        
        Augmented: increased portal blood flow
      - Classification of causes of portal hypertension:
        
        Pre-hepatic: portal vein thrombosis
        
        Hepatic:
        
        Cirrhosis
        
        Non-cirrhotic e.g. portal tract fibrosis due to schistosomiasis
        
        Post-hepatic: obstruction venous outflow from liver = Budd Chiari syndrome (rare)
      - Consequences of Portal Hypertension
        
        Porto-systemic collaterals develop:
        
        Extrahepatic - where portal venous and systemic venous circulations anastomose:
        
        Varices (oesophageal and gastric, risk of bleed)
        
        30% bleed, 30% die, high rate of recurrence
        
        Heavy alcohol users:Remember: not all upper GI bleeds are varices
        
        Variceal bleed:
        
        Resuscitate, drugs to reduce portal blood flow
        
        Prevent/treat complications (aspiration, infection, HE)
        
        Endoscopic treatment of varices by band ligation
        
        Endoscopic sclerotherapy not favoured (complications)
        
        If above fail: placement of TIPS or surgery
        
        Prevention
        
        Primary prevention
        
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        Secondary prevention
        
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        Rectal, periumbilical (‘caput medusae’). Caput medusae is the name for a cluster of swollen veins in your abdomen. The swelling usually appears around the belly button, and the veins branch out from a central point
        
        Shunting of portal venous blood (reduced liver function)
        
        Haemodynamic alterations: Ascites and hepatorenal syndrome
        
        Ascites
        
        Fluid in peritoneal cavity
        
        Cirrhosis commonest cause (>80%)
        
        Haemodynamic changes a/w portal hypertension
        
        Water and salt retention, preferentially accumulates as ascites in cirrhosis associated with portal hypertension
        
        Other causes
        
        Malignancy (ovarian cancer classic, but also GI cancers)
        
        Rare: non-cirrhotic portal hypertension
        
        Rare: heart failure, pancreatitis, TB
        
        Abdominal distension, shifting/flank dullness
        
        Paracentesis = tap of ascites fluid
        
        Diagnostic tap – do cell count, microbiology (blood culture bottles), albumin, cytology
        
        Therapeutic tap - diuretic-resistant ascites in cirrhosis
        
        Treatment
        
        Na+ restriction, diuretics (spironolactone)
        
        Therapeutic paracentesis
        
        Avoid NSAID’s
        
        High index of suspicion for infection (low threshold for paracentesis)
        
        Diuretic-resistant = refractory ascites
        
        Spontaneous Bacterial Peritonitis (SBP)
        
        Infection of ascites fluid without evidence of surgically-treatable intra-abdominal cause
        
        Infection associated with cirrhosis (E. coli, Klebsiella)
        
        Early diagnosis, prompt treatment, better outcome
        
        Subtle/silent presentation
        
        Low threshold for paracentesis of ascites fluid
        
        Suspect:
        
        Fever, abdominal pain/tenderness, altered mental state
        
        Treat if ascites fluid cell count >250 polys/mm3
        
        Antibiotic prophylaxis if high risk (e.g. previous SBP or bleed)
        
        Splenomegaly (congestive)- 20 hypersplenism (low blood counts e.g. Plts)
    - - Stone in CBD (Common bile duct)
      - Tumour (within, at end of, outside compressing)
      - Stricture (PSC or post-intervention)
      - Identify dilated ducts (ultrasound)
      - Identify + treat cause (US, MRCP, EUS, ERCP)
      - Unrelieved, risk sepsis (ascending cholangitis)
      - Obsolete term: = ‘surgical jaundice’
- - - - 7 serogroups (A-G), Group A most common
      - Commonest cause of acute diarrhoeal illness in infants + young children
        
        Main cause of diarrhoea requiring hospitalisation
        
        Outbreaks: crèches, children’s hospitals
        
        Susceptibility greatest between 6 & 24 months
        
        By 3 yrs. most people infected & immune
      - Occasionally seen in the elderly living in long‐term care facilities.
      - Infectious dose very small
      - Incubation period 2-4 days
      - Tropical regions = year round.
      - Temperate climates = peaks during the cooler months
    - - Multiplies in villi of small intestine
        
        Damaged cells slough into lumen of intestine
        
        Release of large numbers of viruses
      - Shortening & flattening of villi- Decreases the surface area for production of enzymes & absorption
      - Hyperosmotic diarrhoea results from this malabsorptive state
    - - Diarrhoea for about 5 days
        
        Variable: mild diarrhoea & vomiting to severe, non-bloody watery diarrhoea with dehydration & electrolyte loss
        
        Dehydration, 12-18 month-olds
        
        Circulatory collapse & death occasionally in severe cases
      - In immunocompromised, may cause persistent diarrhoea
      - Rarely, CNS manifestations
        
        Seizure
        
        Encephalopathy
  - - - Short incubation period (12-72hrs)
      - Acute diarrhoea/ vomiting (more prominent in calicivirus infections)
      - Abdominal cramps/ malaise/ myalgia/ headache
      - Spontaneous resolution in 24-48 hrs
      - Rehydration important
    - - Spread by the faecal-oral route
      - Contaminated water or food
      - numerous outbreaks caused by caliciviruses & astroviruses in bivalve shellfish (oysters, clams, mussels etc.)
      - Replication in small intestine
      - Asymptomatic excretion by carriers is not uncommon
      - Main manifestation: Astrovirus primarily is diarrhoea whereas norovirus is vomiting
    - - Hand hygiene
      - Good standards of environmental cleaning & disinfection
      - In hospitals & other healthcare facilities
        
        Surveillance to detect cases & outbreaks
        
        Isolation / cohorting of patients
        
        Closing wards / limiting traffic (visitors, staff) & transfers
    - - Clinical presentation – especially in healthcare facilities if staff also have symptoms
      - Faeces: PCR (antigen detection, EM, but now much less common)
  - - - Infantile diarrhoea – watery diarrhoea and fever lasting up to 2 weeks
      - Respiratory infection (common), meningitis, conjunctivitis
- - - - Enterovirus: 3 distinct serotypes, Type 1 the most likely to cause paralysis
      - Paralysis in infected individuals: 1 in 1000, higher in adults
      - Faecal-oral spread
        
        Virus multiplies in lymphoid tissue of GIT & migrates to the local lymphatic glands
        
        Continues to multiply in the intestine with faecal excretion
      - Chronic gastrointestinal or respiratory tract carriage does not occur
      - 90% asymptommatic
      - 5% fever, headache, 1-2% aseptic meningitis
      - epidemiology
        
        Humans the only known reservoir
        
        Incubation period: usually 7 days
        
        Faecal-oral spread
        
        Highly infectious as it can remain in stool for up to 6 weeks
        
        Seroconversion in household contacts = 100% kids / 90% + adults
      - Clinical manifestations
        
        3 manifestations
        
        Nil or mild illness (90-95% cases of infection)
        
        but shed virus in stool & are infectious
        
        Influenza-like illness (4-8%)
        
        Fever, lack of energy, pharyngitis…
        
        Complete recovery usually in 1 week
    - - Clinical manifestations
        
        Fever
        
        Common cold
        
        Rash
        
        Herpangina (vesicular ulcerated lesions around soft palate/uvula)
        
        Hand, foot and mouth disease (vesicles)
    - - Clinical Manifestations
        
        Fever
        
        Rash
        
        Meningitis
        
        Epidemic myalgia (Bornholm’s disease) – severe pleuritic chest pain
        
        Respiratory: bronchitis & pneumonia in children
        
        Myocarditis, pericarditis
    - - Clinical Manifestations
        
        Many asymptomatic
        
        Fever
        
        Sore throat with rash
        
        Meningitis
        
        Diarrhoea
        
        Rubella-form rash
        
        Pericarditis, myocarditis
      - At least 33 antigenic types (1 – 33)
      - Spread: faecal-oral route or by oropharyngeal secretions
    - - Enterovirus D68
        
        Non polio enterovirus
        
        Spread
        
        Virus found in infected person’s respiratory secretions
        
        Spread through direct inhalation / manual transfer of infected particles
        
        Cough / Sneeze / Saliva / Fomites
        
        Epidemiology
        
        Cases peak in Summer and Autumn
        
        Children predominantly affected
        
        Underlying respiratory illness (Asthma)
        
        Clinical manifestations
        
        Mild upper respiratory tract infection
        
        Severe LRTI
        
        Acute flaccid paralysis
        
        Diagnosis- PCR (Throat / Nasopharyngeal swab, BAL, CSF)
        
        Treatment
        
        Supportive
        
        No antivirals
- - - - Establish cause
        
        Most H. pylori associated
        
        Others caused by NSAIDs
        
        inflammation of the mucosal lining of the stomach, depletion of the protective alkaline mucus layer and alteration of gastric acidity
      - Remove cause
        
        Management of PUD will depend on whether or not the patient is taking a NSAID.
        
        For people taking a NSAID who also test positive for H. pylori, eradication therapy reduces the additional risk posed by H. pylori above
        
        that posed by the NSAID, i.e., the NSAID is the greatest risk in these patients. Therefore, eradication therapy should commence after 8 weeks of a full dose PPI.
        
        Increase in triple therapy in patients with GORD can increase acidity and risk of adenocarcinoma
        
        Eradication of H. pylori
      - Promote ulcer healing: Acid suppression if ulcer large or complicated haemorrhagic perforation
      - H. Pylori in >50% over 40s. >90% in ME.
      - Patients not taking a NSAID:
        
        Test for H. pylori:
        
        If positive – offer one week eradication therapy
        
        If negative – offer full dose PPI for 4 to 8 weeks
      - Patients taking a NSAID:
        
        Stop the NSAID if possible.
        
        Test for H. pylori:
        
        If positive – treat with full dose PPI for 8 weeks, then offer one week eradication therapy
        
        If negative – treat with full dose PPI for 8 weeks.
      - If symptoms recur after successful treatment, patients should be advised to step down PPI therapy to the lowest dose needed to control symptoms.
      - ‘As-needed’ use of PPIs should also be discussed. If there is an inadequate response to a PPI, a H2 receptor antagonist is advised
  - - - Antacids
        
        Weak bases [alkaline metal salts] acting to neutralise gastric acid and raise gastric pH
        
        Symptom relief in peptic ulcer disease - Rarely facilitate ulcer healing
        
        Used to relieve symptoms of indigestion, dyspepsia, heartburn, GORD
        
        Will raise pH briefly, but body reacts and lowers pH again
        
        Sodium bicarbonate
        
        Rapid neutralisation
        
        Alkalosis
        
        CO2 production
        
        Sodium load
        
        Calcium carbonate
        
        CO2 production
        
        Ca2+ causes gastrin release
        
        CaCO3 – not rapidly absorbed so no alkalosis and no Na load. Worse acid rebound because of Ca release of gastrin.
        
        Can ppt out in alkaline part of lower GIT and cause constipation.
        
        Hypercalcaemia if on for long time – deposition of Ca salts in tissues
        
        Magnesium
        
        Mg(OH)2 rapid neutralisation- produces diarrhoea
        
        Mg2Si3O8 rapid neutralisation- produces silica
        
        MgOH – rapid acting, no CO2, no acid rebound. Milk of magnesia.
        
        Mg2Si3O8 + nH2O + 4H+ = 2Mg + 3SiO2 + n+2H2O
        
        Gelatinous silica deposited on the wall of the stomach and can protect it from damage.
        
        Aluminium
        
        Al(OH)3 slow & poor neutraliser
        
        produces constipation
        
        Al – pH never gets above 3.5
        
        Used in renal dialysis to treat hyperphosphataemia
        
        Mg(OH)2 & Al(OH)3 co-dried gel
        
        Constipation and diarrhoea cancel each other out
        
        no acid rebound
        
        Antacids can alter the absorption of some drugs (including diazepam).
      - alginates
        
        Rafting agent – alginates: These pharmaceutical preparations - most widely known is Gaviscon, contain alginic acid combined with small doses of antacids
        
        Swells and thickens in contact with stomach contents
        
        Floats on top of contents [raft]- providing a mechanical barrier to reflux
        
        When reflux occurs, this viscous foam first contacts the oesophageal mucosa
        
        used to treat Heartburn
  - - - Gastrointestinal irritation
      - Motion sickness
      - Intracranial pathology
      - Pain
      - Drug side effect e.g. Cancer chemotherapy drugs
      - Metabolic disturbance
      - Hormonal e.g. morning sickness in pregnancy
      - Psychogenic factors: horrific sight, foul smell
    - - Regulatory receptor mechanisms (and their Antiemetic drugs) include
        
        Cholinergic [M] - their drug : Anticholinergics
        
        Muscarinic antagonists [vestibular nuclei and VC]
        
        Motion sickness of short duration, e.g. hyoscine (scopolamine) – Joy Rides/Kwells
        
        Little antiemetic effect in other situations
        
        Anticholinergic side effects
        
        Blurred vision
        
        Constipation
        
        Decreased sweating
        
        Dizziness
        
        Dry mouth
        
        Slowing down of urination
        
        Glaucoma is precipitated as intraocular pressure increased so these drugs are contraindicated for patients with glaucoma.
        
        Histaminergic [H1]- their drugs Antihistamines
        
        H1 antagonists [vestibular nuclei]; some also have anticholinergic activity
        
        Motion sickness, e.g., cyclizine
        
        Sedation as a side effect
        
        Dopaminergic [D2] - their drugs D2 receptor antagonists
        
        D2 receptor antagonists [depress CTZ function]
        
        Decrease vomiting due to drugs, e.g. emesis due to cytotoxic drugs [cancer chemotherapy]
        
        Phenothiazines, e.g. prochlorperazine [also M, H1] have multiple effects and multiple targets
        
        Butyrophenones, e.g. haloperidol (has many side effects, off-label use)
        
        Only in radiation sickness, after surgery or in terminal illness
        
        Stimulants of upper GIT motility – emptying
        
        Domperidone; also simulates GIT motility
        
        Peripheral D2 dopamine antagonist; no EPS – does not cross BBB
        
        Stimulates gastric emptying – enhances contraction in stomach
        
        Increases lower oesophageal sphincter tone
        
        Both speed up transit of stomach contents
        
        Cardiac side effects - Ventricular Arrhythmia and Cardiac Death
        
        prolongs QT interval. Not used in US
        
        Used to prevent aspiration in anaesthesia
        
        Also reduce chemotherapy-induced nausea and vomiting
        
        Metoclopramide; also simulates GIT motility. Extrapyramidal side effects; increased prolactin secretion
        
        prevents smooth muscle relaxation produced by dopamine
        
        It also inhibits the release of acetylcholine activating prejunctional D2 receptors, which leads to an indirect inhibition of the musculature and inhibits presynaptic 5-HT4 receptors.
        
        Stimulates gastric emptying /Increases lower oesophageal sphincter tone
        
        EMA – Risk of neurological effects - Extrapyramidal side effects (EPS) (< 5 days treatment) FDA says 12 weeks! . Extrapyramidal system drives muscle spasms, Parkinson-like symptoms, bradykinesia, tremour
        
        Dopamine receptor antagonist- Dopamine has a direct relaxant effect on the gut by activating muscular D2 receptors in the lower esophageal sphincter and stomach (fundus and antrum)
        
        note that Gastroparesis is slowed emptying, leads to nausea, vomiting, bloating
        These drugs speed up gastric emptying.
        
        Serotonergic [5-HT3]
        
        Serotonin receptor antagonists [depress CTZ function; depress visceral afferents from GIT]
        
        Decrease vomiting due to drugs, e.g. emesis due to cytotoxic drugs [cancer chemotherapy] and post-surgery
        
        Ondansetron
        
        Orally or by i.v. infusion with cytotoxics
        
        Side effects
        
        Constipation
        
        Headache
        
        Cannabinoid [CB1]
        
        Delta 9-Tetrahydrocannabinol [Delta 9-THC] analogues acting through cannabinoid [CB] receptor
        
        Decrease vomiting due to drugs that stimulate CTZ
        
        Nabilone- THC mimetic
        
        Side effects
        
        Drowsiness
        
        Psychological effects, including psychotic reactions
        
        Steroids for refractory emesis
      - 5HT4 agonists – improve emptying
        
        5HT3 antagonists – treat nausea
        
        D2 antagonists – increase emptying and depress CTZ to ease nausea/vomiting
  - - - Defense: Mucus Bicarbonate
      - Attack: Acid Pepsin
      - Loss of integrity of barrier: ulceration
- - - - Transmural inflammation
      - Panenteric - Mouth to anus
      - Diarrhoea with or without bleeding
      - Infectious factors
      - Genetic factors
      - Immunological mechanisms
      - TNF alpha- Proinflammatory cytokine
    - - Mucosal and submucosal inflammation
        
        Rectum [always]
        
        Colon [variable]
      - Diarrhoea and bleeding
      - Infectious factors
      - Genetic factors
      - Immunological mechanisms
    - - Aminosalicylates
        
        5-Aminosalicylates Decrease symptoms in mild disease and maintenance treatment prevents relapse in UC / widely used in Crohn’s but evidence limited
        
        Anti-inflammatory agents inhibiting prostaglandin formation and block transcription of inflammatory cytokines (TNF and IL-1) in colonic epithelial cells
        
        Sulfasalazine (prodrug giving mesalazine as active metabolite plus sulfapyridine – antibacterial agent. mesalazine and olsalazine - less toxicity. . Olsalazine is a dimeric prodrug of mesalazine.
        
        Orally or enema
        
        Adverse effects: GIT disturbance; hypersensitivity reactions by sulfapyridine. Blood dyscrasia - thrombocytopenia
      - Corticosteroids
        
        Modulation of immune system; inhibition of cytokine production to induce remission
        
        Response rate of 70-75% in UC and Crohn’s
        
        Risk of relapse on withdrawal and dependency
        
        Prednisolone: p.o., (40 mg) first line
        
        Hydrocortisone: i.v., topical
        
        Budesonide: p.o., low bioavailability, high first pass metabolism gives‘topical’ action
        
        Typical steroid side effects limit long-term use: osteoporosis
        . Other side effects:
        
        hypertension
        
        diabetes,
        
        weight gain,
        
        increased vulnerability to infection,
        
        cataracts and glaucoma (eye disorders),
        
        thinning of the skin,
        
        bruising easily
        
        muscle weakness.
        
        Withdrawal
      - Immunosuppressive agents
        
        Purine analogues inhibiting nucleic acid synthesis for long-term maintenance
        
        Azathioprine (prodrug giving mercaptopurine as active metabolite)
        
        Metabolism pathway of azathioprine: competing pathways result in inactivation by TPMT (Thiopurine S-methyltransferase gene) or XO (Xanthine oxidase), or incorporation of cytotoxic nucleotides into DNA.
        
        TPMT activity is controlled by a genetic polymorphism.
        
        Patients with low or absent TPMT activity (1 in 300 patients) are at an increased risk of developing severe, life-threatening myelotoxicity – reduction of blood cell production
        
        Thiopurine S-methyltransferase gene – TMPT, Hypoxanthine-guanine phosphoribosyltransferase – HGPRT, Xanthine oxidase – XO, Thioinosine monophosphate -TIMP, Inosine monophosphate dehydrogenase – IMPD, GMP synthase – GMPS, 6-methyl mercaptopurine nucleotides – 6-MeMPN, 6-Thioguanine nucleotides – 6-TGN
        
        Mercaptopurine
        
        bone marrow suppression
        
        Not in pregnancy:
        Women exposed to AZA or 6-MP alone or in combination with other Crohn disease medications had higher risks of preterm births (25 percent). Congenital abnormalities occurred in 15 percent of the AZA or 6-MP group
        
        Patients who do not seem to respond to steroids or to 5-ASA may respond to immunosuppressants
        
        Thiopurine analogues - Azathioprine is metabolized to 6-mercaptopurine (6-MP) - interferes with DNA and RNA synthesis. Inhibits the proliferation of T and B lymphocytes.
        
        Slow onset action 2-3 months – not used for flare-ups
        
        Methotrexate inhibits DHFR, AICAR transformylase and thymidylate synthase
        
        Used in Crohn's disease in patients not responding to azathioprine and 6-MP
        
        Methotrexate also may be effective in patients with moderate to severe ulcerative colitis
        
        MTX inhibits DHFR, blocking both (2)and (3) – preventing purine and pyrimidine biosynthesis. Inability to make DNA and RNA blocking protein synthesis. MTX also blocks (4) AICAR transformylase, allowing AICAR to accumulate, which (5) gets broken down to adenosine. Circulating adenosine can then act on A3 receptors, leading to inhibition of neutrophil degranulation. It is these effects thought relevant for uses of MTX in autoimmune conditions.
        
        Mercaptopurine is used less often than azathioprine in the UK.
        
        Some patients who cannot tolerate azathioprine (due to side effects) may still be able to take mercaptopurine.
        
        Thiopurine methyl transferase (TPMT) – test for enzyme activity or genetic test – decreased WBC count can trigger testing
        
        Azathioprine and mercaptopurine increase the skin’s sensitivity to sunlight and the risk of developing some forms of skin cancer.
        
        Aza-Side effects: fever sickness, bone marrow tox etc
        
        5-aminoimidazole-4-carboxamide ribonucleotide
      - Antimicrobials
        
        No evidence in UC – used in secondary complications (abscesses / fistulating Crohn’s)
        
        Interrupt bacterial role in inflammatory process
        
        Metronidazole for 1 month (3 months max). Metronidazole is (oddly) an antibacterial and antiprotozoal agent
      - TNF alpha inhibitors
        
        Antibodies to inflammatory effects of TNF alpha in the gut for refractory Crohn’s disease
        
        Infliximab - infusion reactions. premed anti-histamine and steroids
        
        TNFα and IBS
        
        Cytokine central to inflammatory response
        
        Levels increased in IBS
        
        Activates pro-inflammatory cytokines
        
        Movement of leukocytes into tissues
        
        Macrophages, mast cells and Th1 cells secrete TNF alpha
        
        TNF alpha stimulates macrophages to produce cytotoxic metabolites, increasing phagocytic activity – destroying tissue.
        
        Anti-TNF therapy
        
        For severe UC and Crohn’s
        
        Infliximab binds to soluble and transmembrane TNF (located on T cells) - prevents TNF alpha from binding to its receptors - first biologic approved for use in IBD
        
        Adalimumab is a humanized IgG antibody that binds to TNF alpha . It blocks interaction of TNF alpha with p55 and p75 TNFRs
        
        Golimumab is a humanised anti-TNF Ab
        
        All have ability of lysing cells involved in the inflammatory process including cells expressing TNF alpha
        
        Crohn's disease is the result of an exaggerated response against constituents of the mucosal microflora by T cells, leading to the production of pro-inflammatory cytokines such as TNF alpha
        
        PEG enhances plasma half-life
  - - - Laxative: elimination of soft, formed stool. soft yet well-formed stools are easily passed
      - (Cathartic: copious, fluid evacuation). Cathartics technically accelerate defaecation
    - - Retain water and electrolytes in lumen via hydrophilic/osmotic properties: increase transit via increase bulk
      - Decreased Mucosal absorption of H2O and electrolytes: increase transit via increase bulk
      - increased intestinal motility: decreased H2O and electrolyte absorption via direct effect to increase transit
    - - Fibre-rich diet and other non-pharmacological measures for functional constipation
      - increase stool mass via component polysaccharides
      - increase transit over 1 - 7 days
      - Bran, methylcellulose, ispaghula extracts
      - Adverse effects:
        
        decreased absorption of drugs
        
        Intestinal impaction and obstruction [dry bulk]
        
        Oesophageal obstruction [dry bulk]
        
        Take with generous amounts of water
    - - Increase transit over 1 - 3 hours
      - Adverse effects: Little absorbed but care in children and with renal impairment
      - MgSO4 etc – “saline laxatives”. Chance of death by dehydration, usually when also taking diuretics/bp meds, especially for first dose
      - Can lead to hypermagnesaemia
    - - Direct stimulation of myenteric plexus/mucosa
      - decrease permeability of mucosal surface
      - Coordinated increase in mass movements
      - Decrease in segmentation
    - - Prodrug for active anthracene derivatives
      - Oral - increase transit over 6 - 8 hours
      - Suppository - increase transit over 15 - 30 mins
      - Senna broken down by bacteria in the gut. Anthracenes directly stimulate mesenteric plexus (muscles) to contract.
    - - Oral - increase transit over 6 - 12 hours
      - Suppository - increase transit over 15 - 45 mins
      - Bisacodyl – also an osmotic laxative, frequently given before a scope or surgery.
    - - Do not abuse
      - May be a side effect of other medication
      - Constipation may indicate intestinal pathology
      - Primary importance of fibre-rich diet and other non-pharmacological measures
    - - ICU patients – decrease ventilator days
      - Opioid medications
      - Verapamil
      - Parkinson’s Disease
  - - - Over 3m deaths per year- WHO estimates a further 1m saved by ORT
      - Causes
        
        Enterotoxins (e.g. E. coli, V. cholerae, Shigella, Salmonella)
        
        Rotavirus, norwalk virus
        
        Parasites (e.g. Giardia, Entamoeba)
        
        Many others (deficiencies, autoimmune, IBS, allergic)
    - - Maintain fluid / electrolyte balance
        
        Oral rehydration
        
        NaCl and glucose for infant diarrhoea
      - Use of anti-infective agents
        
        Little role in simple gastroenteritis
        
        Antimicrobial-associated diarrhoea common
      - Use of constipating agents
        
        Diarrhoea may indicate intestinal pathology
        
        Crohn’s disease, ulcerative colitis
        
        Absorbent compounds
        
        Absorb fluids/toxins
        
        Kaolin, pectin, aluminium hydroxide
        
        Another absorbent compound: activated charcoal
        
        Opiates
        
        increase muscle tone and decrease propulsive movements
        
        decrease sensory stimulation for defaecation reflex
        
        Analgesics - morphine and codeine
        
        Opiate derivatives without CNS effects and dependence liability of morphine
        
        Diphenoxylate – can be mixed with atropine
        
        Loperamide - Imodium
        
        Agents that can cause constipation:
        
        Opioid pain relievers like morphine, codeine etc.
        
        Anti-cholinergic agents like atropine,
        
        Trihexyphenidyl antispasmodics like dicyclomine
        
        Tricyclic antidepressants like amitriptyline
        
        Calcium channel blockers used in arrhythmias and high blood pressure such as verapamil
        
        Anti-Parkinsonian drugs - levodopa, dopamine agonists, selegeline, amantadine, anticholinergics, and others