What’s new is Gastroenterology/Hepatology

Dr Rebecca Palmer

Consultant Gastroenterologist and Bowel Cancer Screener Oxford University Hospitals Foundation Trust

Clinical Lecturer in Gastroenterology, University of Oxford

What’s new?

• Hepatitis C is cured

• NAFLD is endemic

• New biologics for Inflammatory Bowel Disease

• Check Point inhibitor associated colitis

• Bowel Cancer Screening• Bowel Scope

What’s new?

• Hepatitis C is cured (at a price)

• NAFLD is endemic

• New biologics for Inflammatory Bowel Disease

• Check Point inhibitor associated colitis

• Bowel Scope

Hepatitis C

Cure for >90% cure• Shorter treatment duration (12weeks)• Single pill formulation• No interferon• Treatment much better tolerated

What is NAFLD?

• Excessive accumulation of hepatic triglyceride in absence of a significant alcohol intake, hepatotropic virus or pharmacological causes

• Hepatic manifestation of the metabolic syndrome

• A histological spectrum:

Steatosis>>steatohepatitis>>fibrosis>>cirrhosis

NAFLD is a disease of our times

Adult BMI status by sexHealth Survey for England 2010-2012

Patterns and trends in adult obesity 7http://www.hscic.gov.uk/catalogue/PUB13219

NAFLD : risk factors and prognosis

• Risk factors for progression of NAFLD include insulin resistance, age, obesity, smoking and persistently raised ALT.

• Patients with simple steatosis have a benign course, with cirrhosis only developing in 1-2% over 15-20 years. However, they are at increased risk of diabetes and CVD

• Patients with NASH and fibrosis have a 12% chance of developing cirrhosis after 8 years.

• Make the diagnosis• Establish metabolic syndrome components• Assess lifestyle• Therapeutic approaches• Liver Biopsy?• Offer clinical trials• Advice and targets• Follow-up

Cobbold et al. Frontline Gastroenterology 2013

A. ↑ ALT +/- other LFT abnormalities

A-1. Lifestyle, Drug and Alcohol Hx and

Intervention. Recheck LFTs and AST in 3/12

Consolidate Lifestyle changes and recheck in 1

year

A-2. Chronic liver disease screen*:

US abdo

Refer Hepatology

Normal Abnormal

Positive liver screen

Negative screen but ↑ ALP

Negative screen but

steatosis on US

A-3. NFS#

Low risk

Weight loss, address

cardiovascular rfs and reassess NFS in

2 years

High or Indeterminate risk

Refer Metabolic Hepatology

B. Steatosis on US

↑ALT Normal ALT

Alcohol cessation, lifestyle

intervention. Recheck 3/12

≥3 metabolic syndrome*

components

<3 metabolic syndrome*

components

C. Isolated ↑GT D. Isolated ↑ALP

Normal GT↑GT

Likely bony origin

Go to A-1.

E. Isolated ↑Bil

Unconjugated, no haemolysis

Conjugated

Likely Gilbert’s

Go to A-1.

Guidelines Summary: Incidental Finding of Abnormal Liver Function Tests

Red Flags: 1. Jaundice 2. Hepatomegaly/irregular liver 3. Splenomegaly 4. Low platelets 5. Low albumin/Prolonged PT# NFS = NAFLD Fibrosis Score- www.nafldscore.com *For components of chronic liver disease screen and metabolic syndrome, please refer to text

Alcohol within

recommended limits

Excessive alcohol

Inflammatory Bowel Disease

• More than 300,000 people in UK have Crohn’s or Ulcerative colitis

• Chronic conditions with no cure medical currently

• UC has significant impact on daily life• Most people with Crohn’s will require surgery• Unmet need for suitable medical treatments• Much research looking for effective targets

Vedolizumab

• Effect of vedolizumab is limited to the gastrointestinal tract with no effect on the trafficking of lymphocytes to other organs including the central nervous system

• Being used in biologic naïve (UC) and those with refractory disease or loss of response to Anti-TNF

• Very good safety profile• Can be slow to have effect (up to 16 weeks)

Biosimilars

• Highly similar and clinically equivalent to the originator biologic (large highly complex structure)

• Infliximab and Adalimumab now off patent

Vedolizumab

• Humanized monoclonal antibody that inhibits adhesion and migration of leukocytes into the gastrointestinal tract by preventing the alpha4beta7 integrin subunit from binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1)

• MAdCAM-1 is preferentially expressed on blood vessels in the intestinal tract

• Vedolizumab is more gut-specific and therefore a more targeted form of immunosuppression

Vedolizumab Humanized anti-alpha-4-beta-7 integrin monoclonal antibody

Check point inhibitor associated Colitis

Ipilimumab (Anti CTLA-4 Ab) Nivolumab (Anti PD-1)

•Diarrhoea occurs typically 6 weeks into treatment•Common - significant colitis approx 5% during Ipilimumab trial•Colitis less common with PD-1 blockade than CTLA-4 blockade

•no prospective trials to guide the treatment of irAEs

•Exclude C. diff and infections

•Treatment with corticosteroids and if not settling with IV hypdrocortisone and endoscopic/histological confirmation colitis consider Infliximab 5mg/kg

Refer to Gastroenterology

Bowel Scope• About one in 20 people in the UK will develop bowel cancer during

their lifetime.• It is the third most common cancer in the UK, and the second

leading cause of cancer deaths, with over 16,000 people dying from it each year

• Lifetime risk of being diagnosed is:– 1 in 20 for women– 1 in 18 for men1

• Regular bowel cancer screening has been shown to reduce the risk of dying from bowel cancer by 16%

(Cochrane Database of Systematic Reviews, 2006. Screening for colorectal cancer using the faecal occult blood test: an update).

Five Year Survival by Dukes stage 2

Disease Course

• Over 90% of bowel cancers are adenocarcinomas, arising from adenomatous polyps

• Studies suggest 1-10% of polyps change to invasive cancers

• Larger size, villous histology and severe dysplasia are important indicators of cancer progression

• Flat adenomas account for 10% and harder to detect

Bowel Scope

• NHS bowel scope screening is a relatively new test to help prevent bowel cancer.

• One off flexible sigmoidoscopy at age 55• The NHS bowel scope launched in 2013• Gradually being rolled out to all men and

women in England aged 55.

Bowel Scope• Home enemas• Nurse endoscopist led

service

Out of 300 people who have bowel scope screening, about 14 will be offered a colonoscopy and polypectomy• >3 polyps• Polyp >10mm• Villous component to polyp

Bowel Scope

NHS bowel scope screening helps to prevent bowel cancer.

For every 300 people screened• 285 will have normal test•two are prevented from getting bowel cancer•saves one life from bowel cancer

What is Bowel Cancer Screening

• Began 2006 with the aim to screen for colorectal cancer across the UK using Faecal Occult Blood Tests.

• For men and women aged:– England – 60-74– Wales & Northern Ireland – 60-74– Scotland – 50-74

• Patients found from the National Health Service registration database covering 98% of the population

• Given 3 FOBT (6 windows) every 2 years.

• Bowel Scope

Evidence for screening

• 4 RCTs of mass screening performed:– UK 5, Denmark 6, USA 7, Sweden 8

– Reduced bowel cancer-specific mortality using biennial, annual screening or a combination with follow up 11 to 18 years.

– Meta-analysis of these 4 RCTs reported• 16% reduction in bowel cancer specific mortality• OR 0.85; CI 0.78-0.93 (for Biennial)

Structure of NHS BCSP• 5 Hubs• 90-100 local screening centres

– Each serving upto 2 million people• Each hub responsible for:

– Perform call/recall services– Testing FOBt kits & dispatch results– Arrange screening nurse clinic appointments at local centre for people

with abnormal results• Local screening center responsible for:

– Manage patients from first screening nurse appointment through investigations to point of discharge.

• Discharge is back to– Screening programme, polyp surveillance programme, GP or

Consultant

Bowel Cancer Screening Info

http://www.cancerscreening.nhs.uk/bowel/publications/video/bowel-screening-kit-cartoon.html

FOBt

• 1 week after invitation letter FOBt kit sent• Freepost envelope to return kit back to hub

laboratory• Kit must be returned within 14 days of first

sample to ensure result can be obtained.• Accuracy– Sensitivity 55-92.2% in RCT’s(Cochrane systematic

review) 9 – Diet does not affect unrehydrated tests(done in UK)

and excessive dietary restrictions can affect uptake 10

What’s done with test results?

Treatment and Surveillance Pathways

Screening outcome-pilots

• FOBt uptake – 59%– Lower uptake in people from Indian subcontinent– Higher uptake in less deprived areas 2

• FOBt results – 1.6% positive – This is after unclear results receiving second and third

tests as well. Also, re testing of failed tests.• Colonoscopy uptake – 78% – For every 16 patients out of 1000 offered colonoscopy

• Colonoscopy results – 10% cancer detection– Adenoma detection 40%– Normal – 50% 2

Further Significant findings 11

• Analysis of first 2.1 million tests (2008 data)– FOBt uptake 55-60%• London was lower at 40%

– Colonoscopy uptake 83%– Early cancer (Dukes A or B) found in 70% of those

with cancer. – On track for 16% mortality reduction found in

RCTs

Problems with FOBT

• gFOBT:– Indirectly detects blood in the stool that may be due

to CRC bleeding– Oxidation of Guaiac by hydrogen peroxide catalysed

by the peroxidase activity of Haemaglobin.– Disadvantages:

• Reaction can occur with any peroxidase in stool (some plants, haem in red meat)

• Is affected by compounds such as vitamin C.• Can detect blood from anywhere in GIT eg stomach.• Requires 6 samples• Visual reading of results by laboratory technicians

Role of Faecal Immunochemical Test

(FIT)• FIT:– Uses an antibody directed against human globulin

(the protein part of Haemaglobin)– Specific for human blood.– More specific for detecting blood from distal gut –

colon/rectum.– 1 sample – stool test placed on card or vial by

wooden stick or brush– Automated laboratory test with numerical result

FIT vs gFOBT: sensitivity/specificity

FIT vs gFOBT: uptakeHigher participation with FIT by 13%

Summary Bowel Screening

• Bowel scope and BCS is beneficial in reducing mortality and is set to grow

• FIT vs gFOBT – FIT is more sensitive and specific – FIT is easier to use and therefore higher uptake rate– FIT could increase the yield of CRC/Adenoma detection

and therefore further reduce Cancer rates• We probably don’t have colonoscopy capacity for an

additional 13% uptake• Need more bowel cancer screeners too• FIT will be introduced April 2019

Rolling out FIT

• Starting sensitivity threshold of 120ug/g (micrograms of blood per gram of faeces) in England = 2%

• extra 1,500 cancers and 8,500 high risk polyps could be detected

• Sub-optimal threshold (20 – 45ug/g, which is far more sensitive is being used in other countries)– significant impact on colonoscopy and pathology services, many units are struggling to

cope with the increasing demand for services.

FIT in the future

• Regular audit and review• Reduction in FIT threshold• Age reduction to 50-74– Inline with Scotland

• Additional 7.5million people in England screened• Paucity of resources• FIT has potential to be a game changerColorectal cancer is a preventable disease

Learning outcomes

• NAFLD should be treated to prevent significant morbidly and mortality

• New biologics for Inflammatory Bowel Disease including introduction of oral novel agents

• Bowel Scope in process of nationwide roll out but may be on the way out

• Bowel Cancer Screening is due to change to will prevent more cancers

Advanced Endoscopic Resection

• Endoscopic resection large colonic/rectal polyps

• Oesophageal endoscopic mucosal resection

• Haemorrhage• Perforation• Post polypectomy syndrome

Specific Techniques Endoscopic mucosal resection (EMR) ESD

http://www.olympus.es/medical/en/medical_systems/applications/gastroenterology_1/treatment_of_lesions/polypectomy___hot_biopsy

/polypectomy.html

Complications

Haemorrhage Immediate <12hrs Delayed >12hrs – 30 days

Perforation Post-polypectomy syndrome

AKA post-polypectomy coagulation syndrome AKA transmural burn syndrome

Haemorrhage Immediate <12hrs (cut electrocautery) Delayed >12hrs – 30 days (coagulation electrocautery)

0.3 – 6% (24% in larger polyps) Greater risk

– Polyps >17mm– Pedunculated polyps with stalks >5mm– Sessile polyps– Malignant polyps– Hypertension

Dobrowolski S, Dobosz M, Babicki A, Głowacki J, Nałecz A. Blood supply of colorectal polyps correlates with risk of bleeding after colonoscopic polypectomy. Gastrointest Endosc 2006; 63: 1004-1009Watabe H, Yamaji Y, Okamoto M, Kondo S, Ohta M, Ikenoue T, Kato J, Togo G, Matsumura M, Yoshida H, Kawabe T, Omata M. Risk assessment for delayed hemorrhagic complication of colonic polypectomy: polyp-related factors and patient-related factors. Gastrointest Endosc 2006; 64: 73-78

Post-polypectomy Syndrome Polypectomy coagulation syndrome/Transmural

burn syndrome Presentation mimics perforation

localised peritonitis, abdo pain, fever, leucocytosis

Caused by transmural injury of bowel wall at site of excised polyp due to over electrical current or thermal injury

CT findings– Focal mural thickening– +/- pericolic fluid– +/- soft tissue stranding of pericolic fat

Post-polypectomy Syndrome Reported in 6 patients of 16 318 colonoscopies

performed 1994-2002 Previously thought 0.5 -1.2% polypectomies In absence of pneumoperitoneum best managed

conservatively– NBM– Abx

Levin TR et al. Complicaitions of colonoscopy in an intergrated health care delivery system. Ann Intern ed 2006; 145:880

http://www.uptodate.com/contents/postpolypectomy-electrocoagulation-syndrome

Suggested bloods to investigate abnormal LFTs

• FBC, LFTs, prothrombin time (beware if bilirubin raised, clotting prolonged or albumin low)

• Fasting lipids and glucose, uric acid (suggestive of metabolic syndrome)

• Hepatitis viral serology (Hep B, C) • Iron studies (to exclude haemochromatosis) • Autoantibodies to exclude autoimmune liver disease

(AMA, Anti SMA, Anti LK)• Serum caeruloplasmin (exclude Wilson’s diease)/slit lamp

BMJ: British Medical Journal Vol. 341, No. 7767, 7 August 2010

Suggested bloods to investigate abnormal LFTs

• NAFLD is the commonest cause of abnormal LFTs, with a prevalence of up to 30%

• Check medical and drug history (including herbal medicines), alcohol intake, and viral hepatitis risk factors

• Alcohol intake of < 2 standard drinks (or < 30g) a day for men and < 1 (< 20g) a day for women are required to diagnose NAFLD

• With NAFLD the ratio of ALT : AST is usually > 2.

BMJ: British Medical Journal Vol. 341, No. 7767, 7 August 2010