1
Q
HNPCC (Lynch)
A
- 4% of CRC
- microsatellite instability
- defect in one of the DNA mismatch repair genes (germline)
- A. dom
- most common extra-intestinal –> endometrial
2
Q
FAP
A
<1% of CRC
-A. dom
3
Q
ischaemic colitis area
A
watershed area - prone to hypo perfusion and ischaemia
-rectosigmoid junction / splenic flexure
4
Q
dysphagia
A
malignant:
- shorter duration
- solid > liquids
- constant & progressive
- older
- ALARM SYMPTOMS
Benign:
- long hx
- both liquid and solids
- intermittent/unpredictable
- younger
- may have alarm symptom (e.g. wt loss in late course)
e. g. eosinophilic oesophagitis/ achalasia/ dysmotility/ benign stricture/ globus hystericus
5
Q
Barretts
A
precursor of adenocarcinoma
-if low grade dysplasia on 2 occasions, 6 mth apart –> endoscopic ablation therapy or close surveillance
-LGD - annual risk progression to adenoca = 1.8%
-HGD - annual progression risk to adenoma = 10%
most effective rx for HGD - combi endoscopic resection & radio frequency ablation (RFA)
-oesophageal endoscopic mucosal resection (EMR) - HGD/Intramucosal carcinoma
6
Q
barretts surveillance
A
recc, but min evidence
1. no dysplasia
< 3cm, no intestinal metaplasia - repeat, more bx -> if still no dysplasia, dc
< 3cm, with intestinal metaplasia - repeat OGD q 3-5 yrs
>3cm - repeat OGD q2-3 yrs
- indefinite
- PPI, repeat OGD in 6 mths - LGD
- repeat OGD in 6 mths –> if still LGD –> RFA or close surveillance (6 mthly OGD) - HGD or T1a adenoca (within mucosa/submucosa)
-MDT discussion
-RFA
-3 mthly f/up for 1 yr, then annually
type 1 b adenoca –> esophagectomy and lymphadenectomy
7
Q
ascitic fluid analysis
A
SBP
- WCC >500
- neutrophil >250
Perf if 2/3
- total protein >10
- glucose < 2.8
- LDH > upper limit of normal for serum LDH
8
Q
SBP
A
most common - E.coli, Klebsiella
- early abx
- discontinue non-selective b-blocker ( ~60% increase in mortality & higher risk of hepatorenal syndrome)
9
Q
hepatorenal syndrome definition
A
- progressive rise in creat >150
- notmal urine sediment. No proteinuria
- absence of shock
- urine Na <10
- cirrhosis with ascites
- no response to 2 days of volume expansion & withdrawal of diuretics
- no nephrotoxic drugs
10
Q
Hepatorenal syndrome
A
Type 1
- 2x increase in creat > 250 within 2 wks
- med survival - few wks
type 2
- diuretic resistant ascites
- slow increase in Cr > 150
- med survival - 6 mths
11
Q
King’s college criteria for liver transplant
A
Acetaminophen induced
- arterial pH < 7.3 OR
- grade 3/4 encephalopathy with PT > 100 & Cr > 340
Non-acetaminophen induced
-PT > 100 OR
Any 3 of:
- age < 10 or > 40
- non-A & non-B viral hepatitis, idiosyncratic drug reaction, Wilsons
- Jaundice > 7 days
- PT > 50 secs
- bili > 180
12
Q
Etoh hepatitis
A
spectrum: fatty liver -> etoh hepatitis > cirrhosis > HCC
Hx; CAGE
ALT/AST >2
Mod leucocytosis (<20,000)
Rx;
R/out -Hep A/B/C, biliary obst, Budd-Chiari
discrimination factor >32 –> high short term mortality –> steroids/pentoxifylline
MELD > 11 - high mortality
discontinue non-selective b-blocker TNF inhibitor (pentoxifylline) prednisone for 1 mth -> taper
13
Q
AI Hepatitis
A
type 1
- SMA, ANA
- AMA, pANCA (helpful if all ab -ve)
- anti-actin ab
- spec 99% / sens 43%
type 2
- anti-LKM
- spec 99%
Mx;
-not req in asymptomatic/min transaminases, gamaglobulin, necroinflammatory
monoRx -pred indefinitely
combi - pred + AZA
14
Q
wernicke’s encephalopathy
A
classic triad in 10%
- ophthalmoplegia (nystagmus)
- ataxia
- confusion
15
Q
hep c genotype 3
A
Sofosbuvir + daclatasvir for 12 or 24 weeks or
Sofosbuvir + ribavirin for 24 weeks or
The combination of sofosbuvir + pegIFN + ribavirin for 12 weeks
16
Q
barretts surveillance
A
No dysplasia: 3–5 years
Low-grade dysplasia: 6–12 months
High-grade dysplasia in the absence of eradication therapy: 3 months.
17
Q
GLP-1
A
NAFLD
LEAN study - In summary, the study concluded that Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies.
18
Q
inactive hepatitis B surface antigen (HBsAg) CARRIER state.
A
– HBsAg and HBcAb are positive. – normal liver enzymes (AST and ALT) – HBeAg and HBV DNA are negative – HBeAb is positive – asymptomatic
19
Q
chronic hepatitis B, which is divided into
- HBeAg positive and
- HBeAg negative
A
HBeAg positive:
– HBsAg positive.
– HBV DNA positive
– liver enzymes are persistently or intermittently elevated
HBeAg negative(Precore mutant):
– HBsAg positive.
– HBV DNA positive
– liver enzymes are persistently or intermittently elevated
20
Q
resolved chronic hepatitis B (Past infection)
A
– HBsAg negative
– HBsAb positive
– normalization of ALT and AST
– very low levels of HBV DNA(less than 10,000 copies/ml)
21
Q
Hep b lab test
A
- surface antigen (HBsAg) is the first marker to appear and causes the production of anti-HBs
- HBsAg normally implies acute disease (present for 1-6 months)
- if HBsAg is present for > 6 months then this implies chronic disease (i.e. Infective)
- Anti-HBs implies immunity (either exposure or immunisation). It is negative in chronic disease
- Anti-HBc implies previous (or current) infection. IgM anti-HBc appears during acute or recent hepatitis B infection and is present for about 6 months
- HbeAg results from breakdown of core antigen from infected liver cells as is therefore a marker of infectivity
22
Q
hep b status and lab
A
- acute Hepatitis B: High titres of IgM anti-HBc.
- chronic Hepatitis B: HbsAg positive, DNA positive, High titres of IgG anti-Hbc.
- Past infection (Not a carrier): HBsAg negative, HbsAb positive, HBeAb positive, core IgG positive, undetectable DNA
- Inactive carrier: HBsAg positive, HBeAb positive, HBcAb positive
- previous immunisation: HBsAb positive, ALL others negative
- Precore mutant: HbeAg negative, HBV DNA positive.
23
Q
H. pylori initial Rx
A
PPI + clarithromycin + amoxycillin for 10-14 days
24
Q
H.pylori failed ppi rx
A
Bismuth-based quadruple therapy: PPI + Bismuth + Tetracycline + Metronidazole for 10-14 days.
Sequential therapy: PPI + Amoxycillin for 5 days, followed by PPI + Clarithromycin + Tinidazole for 5 days.
Susceptibility driven therapy.
Salvage therapy: Levofloxacin (either triple or sequential) or Rifabutin triple therapy.
25
multitarget Stool DNA testing
- KRAS
- NDRG4
- BMP3
- β-actin, plus
- hemoglobin immunoassay.
26
leptin
from adipose
Functions:
1) Inhibits food intake by reducing the expression of neurotransmitters that increase food intake ie: Neuropeptide Y and agouti-related peptide.
2) Increases energy expenditure.
27
Indications for liver transplant
Chronic noncholestatic liver disorders:
- Chronic hepatitis C
- Chronic hepatitis B
- Autoimmune hepatitis
- Alcoholic liver disease
Cholestatic liver disorders:
- Primary biliary cirrhosis
- Primary sclerosing cholangitis
- Biliary atresia
- Alagille syndrome
- Nonsyndromic paucity of the intrahepatic bile ducts
- Cystic fibrosis
- Progressive familial intrahepatic cholestasis
Metabolic disorders causing cirrhosis:
- Alpha-1-antitrypsin deficiency
- Wilson disease
- Nonalcoholic steatohepatitis and cryptogenic cirrhosis
- Hereditary hemochromatosis
- Tyrosinemia
- Glycogen storage disease type IV
- Neonatal hemochromatosis
Metabolic disorders causing severe extrahepatic morbidity:
- Amyloidosis
- Hyperoxaluria
- Urea cycle defects
- Disorders of branch chain amino acids
Primary malignancies of the liver:
- Hepatocellular carcinoma
- Hepatoblastoma
- Fibrolamellar hepatocellular carcinoma
- Hemangioendothelioma
Fulminant hepatic failure
Miscellaneous conditions:
- Budd-Chiari syndrome
- Metastatic neuroendocrine tumors
- Polycystic disease
Retransplantation
28
Specific recommendations on liver transplant
Hepatocellular carcinoma
– single lesion between 2 to 5 cm or
– no more than three lesions, the largest of which is less than 3 cm, and no radiographic evidence of extrahepatic disease.
– Liver transplantation should be viewed as the treatment of choice for selected patients with hepatocellular carcinoma who are not candidates for surgical resection and in whom malignancy is confined to the liver
Cirrhosis:
– referred for transplantation when they develop evidence of hepatic dysfunction (Child Pugh Score > 7 and MELD > 10) or when they experience their first major complication (ascites, variceal bleeding, or hepatic encephalopathy).
Hepatorenal syndrome:
– Patients with type I hepatorenal syndrome should have an expedited referral for liver transplantation
Morbid obesity (BMI >40 kg/m2) is a contraindication to liver transplantation
Alcoholic liver disease
– delay transplantation for a minimum of 3 to 6 months of abstinence from alcohol
29
Screening prior to liver transplant
1) Dobutamine stress ECHO if chronic smokers, age >50, clinical or family history of heart disease or diabetes.
Positive test confirmed with cardiac catheterization
2) Doppler ECHO for pulmonary hypertension- done to ALL patients.
3) Screen for osteoporosis in ALL patients
30
prognosis indicators for alcoholic hepatitis
Prognosis could be calculated based on the Child-Pugh score and MELD score.
```
The MELD score is based on objective measures (serum bilirubin, creatinine, and PTT) and the
Child-Pugh class is based on both objective and subjective measures (serum albumin, PT, serum bilirubin, degree of ascites, and encephalopathy).
```
31
Hepcidin and ferroportin regulate systemic iron absorption by
Ferroportin stimulates iron release from enterocyte into the bloodstream
Hepcidin inhibits iron release from enterocyte into bloodstream.
32
Extraintestinal manifestations of IBD that are associated with active GI disease
Oral ulcers
Erythema nodosum
Large joint arthritis
Episcleritis.
33
Extraintestinal manisfestations of IBD that are independent of GI disease
```
Primary sclerosing cholangitis
Ankylosing spondylitis
Uveitis
Pyoderma gangrenosum
Kidney stones
Gallstones
```
34
Crohn’s disease - genetic variants --> early initial surgery due to stricturing disease
Nod2/CARD15 variants are associated with early initial surgery due to stenosis and with surgical recurrence in Crohn’s disease.
Patients with these variants could benefit from preventive and/or early therapeutic strategies.
35
Ustekinumab
human monoclonal antibody against IL-12 and IL-23
-correlated with autoimmunity disorders such as RA, lupus, colitis, and inflammatory bowel disease.
36
IBD serological markers
Positive pANCA + Negative ASCA = UC (97% specific)
| Positive ASCA + Negative pANCA = Crohns (97% specific)
37
HNPCC risk of malignancy
high risk of developing cancer of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin.
Women with HNPCC have a 80% lifetime risk of endometrial cancer.
38
Risk factors for oesophageal adenocarcinoma
```
Male sex
Caucasian
Age
Barrett’s esophagus
Obesity
Smoking
Frequent GORD symptoms
Medication that reduces LOS pressure
Absence of H.pylori infection
```
39
Vedolizumab
humanized monoclonal antibody that binds to integrin α4β7 on the surface of the T-lymphocyte and by blocking the α4β7 integrin, this results in gut-selective anti-inflammatory activity (inhibits trafficking of leucocytes to the site of inflammation).
40
PSC
assoc UC
41
Indications for surgery in Ulcerative colitis
- Urgent colectomy is indicated for patients with uncontrolled hemorrhage, severe colitis failing to respond to aggressive medical management within two weeks, or complications such as toxic megacolon or bowel perforation.
- Elective colectomy is indicated in patients who are unresponsive to or cannot be weaned from glucocorticoids, who experience unwanted side effects (eg, growth failure from steroids), or who have surveillance biopsies that suggest a risk for developing cancer
42
Hep B in pregnancy
1. Women with mild liver disease and low viremia should commence treatment only after becoming pregnant.
2. Women with moderate liver disease but no cirrhosis should be treated before pregnancy and if responds to treatment, this could be stopped before pregnancy.
3. Women with advanced liver disease should be treated before and during pregnancy and continue treatment after delivery.
4. Women with mild liver disease but with very high viremia should be treated in the last trimester with a ‘B’ category drug such as Tenofovir but discontinue this after delivery (post-partum).
43
Causes of vitamin B12 deficiency
Dietary:
– vegan
Gastric:
– pernicious anemia
– atrophic gastritis
– gastrectomy
```
Small bowel:
– bacterial overgrowth
– pancreatic insufficiency
– crohn’s disease
– blocking agents- neomycin
```
44
nutrient absorption sites
Absorption of the majority of nutrients takes place in the jejunum, with the following notable exceptions:
– Iron is absorbed in the duodenum.
– Vitamin B12 and bile salts are absorbed in the terminal ileum.
– Water and lipids are absorbed by passive diffusion throughout the small intestine.
– Sodium is absorbed by active transport and glucose and amino acid co-transport.
– Fructose is absorbed by facilitated diffusion.
45
clinical B12 deficiency test
Biochemically, B12 deficiency will have high levels of MMA(98% sensitive) and homocysteine(96% sensitive).
46
Functional constipation dx
The diagnostic criteria includes the following:
At least 12 weeks, which need not be consecutive, in the preceding 12 months of two or more of:
(1) Straining in >1/4 defecations
(2) Lumpy or hard stools in >1/4 defecations
(3) Sensation of incomplete evacuation in >1/4 defecations
(4) Sensation of anorectal obstruction/blockade in >1/4 defecations
(5) Manual maneuvers to facilitate >1/4 defecations (e.g., digital evacuation, support of the pelvic floor)
(6) <3 defecations/week.
47
coeliac disease
TIP: If patient presents with iron deficiency anemia, ALWAYS think of celiac disease (irrespective of age)
– very prevalent.
– may present and diagnosed at any age
Diagnosis: abnormal small bowel biopsy while consuming gluten and following gluten free diet, shows recovery of histology.
– biopsy taken from distal duodenum or jejunum while gluten is being consumed (4 slices of bread/day for 1 month)
– immunosuppression may cause false negative.
Celiac Serology(Supportive of diagnosis):
* Negative serology does NOT exclude celiac disease in High risk(diarrhea, weight loss, anemia) patients
1) Tissue transglutaminase Ab (IgA-tTG)(most accurate) or Endomysial Ab (IgA-EMA).
2) Anti-gliadin Ab (less sensitive/specific)
3) Total IgA level (need to exclude IgA deficiency)
– proceed with biopsy if tTG-IgA positive.
– Treatment is with strict life long gluten free diet (barley, rye, oats, wheat)
– Disease associations: dermatitis herpetiformis, autoimmune conditions (IgA deficiency, IDDM, liver disease).
Clinical pearl: If patient continues to lose weight despite being on gluten free diet, think of small bowel T cell lymphoma.
48
azathioprine s/effect
```
– myelosuppression
– hepatitis
– pancreatitis
– N+V
– infection
– lymphoma
```
49
Gastrinoma
- neuroendocrine tutor > secretes the hormone gastrin --> hypersecretion of acid.
- suspected when ulcers are present in a patient who has a negative test for Helicobacter pylori and who does not take NSAIDs.
Initial test: serum gastrin; a gastrin concentration of > 1000 pg/mL (1000 ng/L) --> highly suggestive of a gastrinoma, but gastrinoma may be present with gastrin levels as low as 150 to 200 pg/mL (150 to 200 ng/L).
After the diagnosis of gastrinoma is made by detecting hypergastrinemia, various tests are used to localize the tumor and to evaluate for metastases.
- CT abdo/pelvis - may miss small pancreatic gastrinomas. - Endoscopic ultrasonography - most sensitive test for pancreatic endocrine tutors - may miss tumors that are not localized within the pancreas.
- Somatostatin receptor scintigraphy - MOST SENSITIVE procedure for identifying the primary gastrinoma and detecting whether metastatic disease is present
50
H.pylori
risk of 1% of gastric MALT lymphoma
| Eradication therapy for H. pylori infection alone results in lymphoma regression in up to 80% of affected patients.
51
GORD
transient relaxations of the lower oesophageal sphincter.
– Presents with heartburn.
– Endoscopy is first choice.
– Ambulatory pH monitoring useful if no response to initial treatment.
– PPI most efficacious.Should have at least 4-8 weeks in initial treatment phase.
– Case report of increased risk for hip fracture with long term PPI.
52
pernicious anaemia
intrinsic factor
anti-intrinsic factor (IF) antibodies:
- sensitivity of 50 to 70%
- specificity ~ 100%
53
Dietary B12
bound to R proteins, liberation depends on pancreatic enzyme
54
achalasia
– Absence of LES relaxation and esophageal peristalsis.
– Typically dysphagia to both solid AND liquid
– Gold standard for diagnosis of achalasia is with esophageal manometry.
– Manometry will show absence of LES relaxation and Hypertensive LES(>45mmHg)
– Treatment is with surgical lower esophageal myotomy(best treatment)
– Other options include botox,pneumatic balloon dilation.
55
Barretts
def:
– Metaplasia of esophageal squamous to columnar epithelium
– Columnar lined (intestinal metaplasia) esophagus is precursor to adenocarcinoma.
Risk factors:
- Chronic GERD(?biggest risk factor)
- Age >50
- Overweight
- Higher socioeconomic status
- Alcohol
- Smoking
Management of Barrett’s esophagus:
– After initial diagnosis, repeat scope in 12 months to ensure no dysplasia.
– If no dysplasia on biopsy on 2 scopes- do 3 year follow up gastroscopy.
– If no dysplasia, treat with high dose PPI long term.
Consider antireflux surgery.
– If low grade dysplasia: repeat scope within 1 year follow up until no dysplasia.
– If High grade dysplasia: surgical resection if medically fit. If not, then consider 3 monthly close endoscopic surveillance or endoscopic ablative therapy.
56
Primary biliary cirrhosis
chronic progressive cholestatic liver disease of unknown cause. It is an autoimmune disorder that occurs predominantly in women (80% to 90% of cases) between 40 and 60 years of age. The diagnostic triad associated with primary biliary cirrhosis includes a cholestatic liver profile, positive antimitochondrial antibody titers, and compatible histologic findings on liver biopsy. Serum alkaline phosphatase level is usually elevated ten times or more above normal. The patient’s near normal alkaline phosphatase concentration and negative antimitochondrial antibody essentially rule out primary biliary cirrhosis.
57
Primary sclerosing cholangitis
chronic cholestatic liver disease of unknown cause that is characterized by progressive bile duct destruction and may lead to secondary biliary cirrhosis. Laboratory findings include a cholestatic liver profile, with serum alkaline phosphatase levels three to five times greater than normal and mild hyperbilirubinemia. This patient’s alkaline phosphatase level is minimally elevated making primary sclerosing cholangitis unlikely.
58
drugs tend to cause a hepatocellular picture
* paracetamol
* sodium valproate, phenytoin
* MAOIs
* halothane
* anti-tuberculosis: isoniazid, rifampicin, pyrazinamide
* statins
* alcohol
* amiodarone
* methyldopa
59
drugs tend to cause cholestasis (+/- hepatitis)
* oral contraceptive pill
* antibiotics: flucloxacillin, Augmentin, erythromycin*, nitrofurantoin
* anabolic steroids, testosterones
* phenothiazines: chlorpromazine, prochlorperazine
* sulphonylureas
* fibrates
* rare reported causes: nifedipine
60
drug causing Liver cirrhosis/fibrosis
* methotrexate
* methyldopa
* amiodarone
61
Autoimmune Hepatitis
– In type I there is an association with other autoimmune diseases (e.g. pernicious anaemia, thyroiditis, coeliac disease and Coombs-positive haemolytic anaemia),
– Pathogenesis is unknown but probably a viral attack that causes a sequence of T cell mediated events against liver antigens, producing a progressive necroinflammatory process which results in fibrosis and cirrhosis.
– In the teens and early twenties the disease (often type II) presents as an acute hepatitis with jaundice and very high aminotransferases, which do not improve with time.
– Patient may range from being asymptomatic to presenting with fatigue and findings of cirrhosis with hepatosplenomegaly, cutaneous striae, acne, hirsuties, bruises and, sometimes, ascites.
```
Lab findings:
– High serum aminotransferases
– Lesser elevations in the ALP and bilirubin.
– High serum gammaglobulins particularly the IgG.
– High prothrombin time.
– Mild normochromic normocytic anemia
– Thrombocytopenia
– Leucopenia
```
Type I:
(a) anti-nuclear (ANA)
(b) anti-smooth muscle (anti-actin)
(c) soluble liver antigen (anti SLA/LP) – 10-30% cases.
This occurs most frequently in girls and young women.
Type II:
anti-liver/kidney microsomal (anti-LKM1).
The main target is cytochrome P4502D6 (CYP2D6) on liver cell plasma membranes.
Treatment:
– Prednisone as induction and Azathioprine as maintenance
– Mycophenolate, ciclosporin and tacrolimus(resistant cases)
– Treatment is lifelong
– Consider liver transplant if treatment fails.
62
Predictive factors for variceal hemorrhage
1) Variceal pressure
2) Location of varices
3) Size of varices
4) Appearance of varices
5) Clinical features of the patient
63
Contraindications to liver transplantation
1) Cardiopulmonary disease that cannot be corrected and is a prohibitive risk for surgery
2) Malignancy outside of the liver within five years of evaluation (not including superficial skin cancers) or not meeting oncologic criteria for cure
3) Active alcohol and drug use. Patient must be abstinence for at least 6 months with participation in a structured rehab program.
64
HNPCC mutation
MSH2 & MLH 1 most common
| hallmark : DNA mismatch repair --> microsatellite instability (MSI- H)
65
infliximab moa
bind to TNF
66
interferon/ribavirin contraindication
- decompensated cirrhosis
- pregnancy
- uncontrolled depression
- unstable cardiac/pulmonary condition
67
increased risk of colon ca gene
DNA mismatch repair (MMR) gene
68
Gi hormones
Gastrin from G cells = “G for Gastrin”
CCK from I cells = “I love hot ChiCKs”
Secretin from S cells = “Secret Secretary”
Somatostatin from D cells= “I’m So Drunk”
69
most common side effect of ribavirin treatment?
Haemolytic anaemia
| Teratogenic
70
Acute hep c rx
Interferon alfa-2b (5 million U) of subcutaneously daily for 4 weeks and then three times per week for 20 weeks.
71
Contraindications for Interferon
```
– significant psychiatric illness
– non compliance
– alcohol intake > 7 standard drinks per week
– pregnancy/lactation
– decompensated cirrhosis
– unable to tolerate low Hb
– solid organ transplant
```
72
Interferon s/effects
```
– flu like symptoms
– neuropsychiatric ie: depression, anxiety
– insomnia
– leucopenia and thrombocytopenia
– weight loss
– hair loss
```
73
Portal hypertension defined as
1) Portal vein pressure above the normal range of 5 to 10 mm Hg
2) Portal vein – Hepatic vein pressure gradient greater than 5 mm Hg (>12 clinically significant for portal hypertension)
74
hypergastrinaemia Causes
1) Prolonged acid inhibition- proton pump inhibitors,H2-receptor antagonist.
2) Atrophic gastritis- pernicious anemia, H.pylori.
3) Vagotomy or small bowel resection
4) Gastrin secreting tumor (ZES)
5) Renal failure
6) Hypercalcemia
7) Hyperlipidemia (artefactual)
75
Autoimmune pancreatitis
– very rare disorder
– associated with Sjogren’s, PBC and RA
– Raised serum IgG4
– Responds to steroids
76
Coeliac dis
HLA-DQ2 or DQ8 is associated in 99.6% of patients with coeliac disease.
They have a strong negative predictive value.
Gene test is only useful if result is negative.(Only useful to exclude celiac)
Very useful to RULE OUT Coeliac disease
