Chronic Idiopathic Intestinal Pseudo-obstruction

Intestinal disorder that mimic intestinal obstruction in absance of mechanical blockage.
Low prevalence < 1 in 2000

this exclude the following conditions:
mechanical obstruction: adhesions, volvulus
colonic pseudo-obstruction:Ogilivie's syndromw
acute adynamic status: ileus
secondary pseudo-obstruction: scleroderma, paraneoplastic, IDDM, radiation, amyloid.

symptoms:
abdominal pain, distention, epidodic N/V, severe constipation, diarrhea, Wt loos.

investigation:
exclude secondary causes
small bowel manometry
full thickness biopsy

treatment:
nutrition (entral/ parentral)
analgesia
prokinatics
antibiotics
immunotherpy
sutgery in selected cases
psychlogical support
palliative care

question colon 2

A middle-aged woman presents with recent changes in her bowel habits. She is investigated as a case of sporadic colonic carcinoma.

What is the mechanism of its tumorogenesis?

1- APC gene mutation

2-beta catenin suppresion

3-down regulation of p27

4-K-ras suppression

5-p53 upregulation

randum questions

Wilson's disease (hepatolenticular degeneration)

Dietary copper is normally absorbed from the stomach and upper small intestine. It is transported to the liver loosely bound to albumin. Here it is incorporated into apocaeruloplasmin, a glycoprotein synthesized in the liver, to produce caeruloplasmin which is secreted into the blood. Copper is normally excreted in the bile.

Wilson's disease is a very rare inborn error of copper metabolism that results in copper deposition in various organs, including the liver, the basal ganglia of the brain and the cornea. Autosomal recessive, incidance 1in 30000. It is potentially treatable and all young patients with liver disease must be screened for this condition.

Aetiology

Autosomal recessive disorder with a molecular defect within a copper-transporting ATPase encoded by a gene (designated ATP7B) located on chromosome 13. It occurs world-wide, particularly in countries where consanguinity is common. There is a failure of both incorporation and biliary excretion of copper. In the liver, copper is incorporated into caeruloplasmin and then excreted with bile. There is a low serum caeruloplasmin in over 80% of patients owing to poor synthesis, but the precise mechanism for the failure of copper excretion is not known.

The liver histology is not diagnostic and varies from that of chronic hepatitis to macronodular cirrhosis. Stains for copper show a periportal distribution but this can be unreliable. The basal ganglia are damaged and show cavitation, the kidneys show tubular degeneration, and erosions are seen in bones.

Pathology

Clinical features

Children usually present with hepatic problems, whereas young adults have more neurological problems, such as tremor, dysarthria, involuntary movements and eventually dementia. The liver disease varies from episodes of acute hepatitis, especially in children, which can go on to fulminant hepatic failure to chronic hepatitis or cirrhosis.

Typical signs are of chronic liver disease with neurological signs of basal ganglia involvement. The presence of neurological fidings is almost synonymous with cirrhosis. A specific sign is the Kayser-Fleischer ring, which is due to copper deposition in Descemet's membrane in the cornea. It appears as a greenish brown pigment at the corneoscleral junction just within the cornea. Identification of this ring frequently requires slit-lamp examination. It may be absent in young children. 95% of patients with neurologic or psychiatric presentation have Kayser-Fleischer ring. Copper deposition in the lens leads to sunflower cataract, which does not interfer with vision. Proximal renal tubular acidosis, nephrocalcinosis, aminoacidurea and hypouricaemia. Chondrocalcinosis, OA, oesteomalcia, oesteoprosis. Blue nails

Investigations

Serum copper and caeruloplasmin Extremely low level of caeruloplasmin should be taken as strong evidance for the diagnosis of WD, but normal level does not exclude the diagnosis. Decrease total serum copper but increase in free non-caeruloplasim bound copper. Urinary copper is usually increased (100-1000 mg in 24 hours; normal levels < 40 mg in 24 hours). Liver biopsy. The diagnosis depends on measurement of the amount of copper in the liver, although high levels of copper are also found in the liver in chronic cholestasis. Measurement of 64Cu incorporation into the liver may be helpful. Haemolysis and anaemia Coomb negagtive may be present (gall stones). Genetic analysis is limited as already over 200 mutations have been identified at the ATP7B locus. low ALP/low serum uric acid may occur in asymptomatic disease or neurological disease (due to Fanconi syndrome).

Treatment

Lifetime treatment with penicillamine, 1-1.5 g daily, is effective in chelating copper. If treatment is started early, clinical and biochemical improvement can occur. Urine copper levels should be monitored and the drug dose adjusted downwards after 2-3 years. Serious side-effects of the drug occur in 10% and include skin rashes, leucopenia and renal damage. Need to supplement pyridoxine Trientine is the second line treatment for patients intolerant to penicillamine. Oral Zinc is the third line. It compete eith copper for intestinal absorption. Tetrathiomolybdate suitable for severe neurologic WD Avoid chocolate, shellfish, liver, nuts, mushrooms. All siblings and children of patients should be screened and treatment given even in the asymptomatic if there is evidence of copper accumulation.

Prognosis

Early diagnosis and effective treatment have improved the outlook. Neurological damage is, however, permanent. Fulminant hepatic failure or decompensated cirrhosis should be treated by liver transplantation. Copper metabolism, my gastro room blog

gastroenteropancreatic neuroendocrine tumours (NETs)

Gastroenteropancreatic NETs may be classified into non-functioning tumours, which have no hormone-related clinical features, and functioning tumours, which cause symptoms due to peptide and hormone release. 

In all NETs, presenting features may include non-specific symptoms such as:

-pain (which may be intermittent and present for many years), Pain may be due to local tumour invasion,

-nausea and vomiting,

-anaemia due to intestinal blood los

Most gastroenteropancreatic NETs are non-functioning and present with
mass effects of the primary tumour or metastases (usually liver).

A high index of suspicion is needed to identify patients, and diagnosis is often delayed for several years, often made as an incidental finding at surgery or during radiological

1-Non-functioning gastroenteropancreatic NETs:

Usually asymptomatic

Gastric and rectal NETs are often diagnosed coincidentally at endoscopy, or may be the source of anaemia.

2-Functioning gastroenteropancreatic NETs:
Because GNETs are of neuroendocrine origin, they may secrete various peptides and hormones. Most of these tumours produce several hormones , but very few are associated with clinical syndrome. Symptoms depend on the peptide hormone released.

Carcinoid syndrome

These originate from the enterochromaffin cells (APUD cells) of the intestine. They make up 10% of all small bowel neoplasms, the most common sites being in the appendix, terminal ileum and the rectum. It is often difficult to be certain histologically whether a particular tumour is benign or malignant. Clinically most carcinoid tumours are asymptomatic until metastases are present. 10% of carcinoid tumours in the appendix present as acute appendicitis, the inflammation being secondary to obstruction. Surgical resection of the tumour is usually performed.

Carcinoid syndrome occurs in only 5% of patients with carcinoid tumours and only when there are liver metastases.The bioactive product is secreted directly into the hepatic vein bypassing inactivation by the liver. Clinical features: Spontaneous or induced bluish-red flushing,without sweating predominantly on the face and neck(70%). Gastrointestinal symptoms consist of : intermittent abdominal pain(40%), and recurrent watery diarrhoea(50%). Cardiac abnormalities are found in 50% of patients and consist of pulmonary stenosis or tricuspid incompetence. Examination of the abdomen reveals hepatomegaly.

The tumours secrete a variety of biologically active amines and peptides, including serotonin (5 -hydroxytryptamine; 5-HT), bradykinin, histamine, tachykinins and prostaglandins.

The diarrhoea and cardiac complications are probably caused by 5-HT itself, but the cutaneous flushing is thought to be produced by one of the kinins, such as bradykinin, which is known to cause vasodilatation, bronchospasm and increased intestinal motility.

Diagnosis and treatment

-Role out MEN1, MEN2 and NF1 -Ultrasound examination confirms the presence of liver secondary deposits. -Chromogranin A is the only general marker for NETs -The major metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), is found in high concentration in the urine. -Octreascan-octreotide scintigraphy can identify the primary tumour and secondaries in 80%.

Octreotide and lanreotide are octapeptide somatostatin analogues that have been shown to inhibit the release of many gut hormones. They alleviate the flushing and diarrhoea and can control a carcinoid crisis. Octreotide is given subcutaneously in doses up to 200 μg three times daily initially; a depot preparation 30 mg every 4 weeks can then be used. Lanreotide 30 mg is given every 7-10 days, or as a gel 60 mg every 28 days.

Long-acting octreotide also sometimes inhibits tumour growth and, since its introduction, other therapy is usually unnecessary. Interferon and other chemotherapeutic regimens occasionally reduce tumour growth, but have not been shown to increase survival. Most patients survive for 5-10 years after diagnosis. Pancreatic NET: 1- Gastinoma: gastrin producing tumour Rare, few than 1% of patients presenting with PUD Frequently associated with MEN1 50% of gastinomas occur in the duodenal wall, and the second common place is the pancreas. result in hypersecretion of acid which result in severe PUD, maily multiple duodenal ulcers. 50% have diarrhea due to the effect of acid in small bowel. If a patient present with duodenal ulcer which is not due to H pylori infection or NSAIDs, or present with the ucer and diarrhea, the concurrent presence of gastrinoma should be considered. Surgical resection is the treatment of choice for patients with resectable disease. If resection is not possible, medical treatment consist of PPI and octreotide. 2-insulinoma: insulin secreting ilet tumour that cause hypoglycaemia. 3-VIPoma: pancreatic tuomour that secrete vasoactive intetinal polypeptide. the syndrome is characterized by;  severe watery diarrhea, hypokalaemia, and achlorohydria (Vernaer-Morison syndrome)

question colon 1

A 20-year-old man was found to have iron deficiency anaemia when he went to donate blood. The Blood Transfusion Service contacted his general practitioner, who referred the patient to the outpatient clinic for further investigation.
Generally, the patient was very well. He had a good appetite, his weight was steady and he ate a normal diet. He had a normal bowel habit and had never passed any blood, mucus or diarrhoea in his stools. The patient denied knowledge of any overt blood loss from any other source.
His general practitioner had organised an open access endoscopy which was normal; duodenal biopsies were unremarkable. He had a limited knowledge of his family history as his mother had died in childbirth and as a result he was an only child. His father had died of what he thought was secondary liver and lung cancer but he was unsure.
On general physical examination he was fit and athletic. The skin and mucosal membranes were unremarkable. Pulse was 70 beats per minute and regular with a blood pressure of 132/78 mmHg. Heart sounds were normal and the chest was clear. His abdomen was soft and non-tender with no palpable masses or organs. Rectal examination was normal. On viewing the rectal mucosa through a rigid sigmoidoscope the colonic mucosa was covered in innumerable polyps.

What specific genetic abnormality is responsible for this appearance?
(Please select 1 option)
1-Germline mutation of the STK11 gene on chromosome 19
2-Homozygous mutation of the MYH gene
3-Loss of the APC gene on chromosome 5
4-Mutations in mismatch repair genes (e.g. MSH2)
5-Mutation of the p53 tumour suppressor gene

Staging of Colorectal Cancer

TNM Staging
Primary Tumor (T)
TX – primary tumor cannot be assessed
T0 – no evidence of primary tumor
Tis – carcinoma in situ: intraepithelial or invasion of lamina propria
T1 – tumor invades submucosa
T2 – tumor invades muscularis propria
T3 – tumor invades through muscularis propria into subserosa or into nonperitonealized pericolic or perirectal tissues
T4 – tumor directly invades other organs or structures and/or perforates visceral peritoneum

Regional Lymph Nodes (N)
NX – regional lymph nodes cannot be assessed
N0 – no regional lymph node metastasis
N1 – metastasis in one to three regional lymph nodes
N2 – metastasis in four or more regional lymph nodes

Distant Metastases (M)
MX – distant metastasis cannot be assessed
M0 – no distant metastasis
M1 – distant metastasis

Summary of recommendation for CRC screening and surveillance

                                             high risk group

                                            moderate risk group

How Does Colorectal Cancer Develop?

Guideline on surveillance following detection of colorectal adenoma

List of recommendations from the BSG/ACPGBI/PHE Post polypectomy and post-colorectal cancer resection surveillance guidelines: 1. We recommend that the high-risk criteria for future colorectal cancer (CRC) comprise either: - two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10mm in size or containing any grade of dysplasia, or an adenoma of at least 10mm in size or containing high-grade dysplasia) - or five or more premalignant polyps. 2. We suggest that where histological completeness of excision cannot be determined in patients with non-pedunculated polyps of 10–19mm in size, or an adenoma containing high grade dysplasia, or a serrated polyp containing any dysplasia, then a site check should be considered within 2–6 months. The need for subsequent surveillance should then be determined based on the high-risk surveillance criteria. 3. We recommend that polyp size should be recorded as the largest dimension of neoplastic tissue (adenoma or serrated) as measured at histopathological examination. For piecemeal resection or where there has been fragmentation of tissue during retrieval, endoscopic assessment of size should be used. 4. We recommend that people with high-risk findings on index colonoscopy who are under the age of 75 years should have a surveillance colonoscopy performed after an interval of 3 years (note the one exception in the next statement) 5. We suggest that due to the long timeline from a clearance colonoscopy through the potential development of new polyps to the possible development of a symptomatic cancer, surveillance should only be performed in people whose life-expectancy is greater than 10 years, and in general not in people older than about 75 years. 6. We recommend that people with no high-risk findings on index colonoscopy should not undergo colonoscopic surveillance, but should be strongly encouraged to participate in their national bowel screening programme when invited (note the one exception in the next statement). 7. We suggest that people with premalignant polyps but no high-risk findings on index colonoscopy, who are more than 10 years younger than the national bowel screening programme lower age-limit, should be considered for a surveillance colonoscopy performed after an interval of 5 or 10 years, individualised to their age and other risk factors. 8. We recommend that patients who have undergone a potentially curative CRC resection should have a clearance colonoscopy within a year of their diagnosis 9. We recommend that once a clearance colonoscopy has been performed in the postoperative period in patients who have had a CRC resection, their next surveillance should be performed after an interval of 3 years. The need for further surveillance should then be determined in accordance with the post-polypectomy high-risk criteria. 10. We recommend that as recurrence rates after pathologically en bloc R0 endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) of large nonpedunculated colorectal polyps (LNPCPs) or early polyp cancers are low, no site checks are required, and the patient should undergo post-polypectomy surveillance after an interval of 3 years. The need for further surveillance should then be determined in accordance with the postpolypectomy high-risk criteria. 11. We recommend a site check is performed 2–6 months after piecemeal EMR or ESD of LNPCPs (at least 20mm in size), in line with BSG/ACPGBI LNPCP guidelines. A further site check at 18 months from the original resection is recommended to detect late recurrence. Once no recurrence is confirmed patients should undergo post-polypectomy surveillance after an interval of 3 years. The need for further surveillance should then be determined in accordance with the post-polypectomy high-risk criteria 12. We recommend that the need for ongoing colonoscopic surveillance should be determined by the colonoscopic findings at each surveillance procedure, using the same high-risk criteria to stratify risk. 13. We recommend that people with high-risk findings on a surveillance colonoscopy should undergo a further surveillance colonoscopy at an interval of 3 years (with the same age related caveats applied again). 14. We recommend that people with no high-risk findings on a surveillance colonoscopy should cease colonoscopic surveillance, but should participate in the national bowel screening programme when invited (with the same age-related caveats applied again). 15. We recommend that surveillance colonoscopies should only be performed by colonoscopists who are either screening accredited, or whose colonoscopy performance measures (key performance indicators—KPIs) exceed the minimum standard as defined in the BSG lower gastrointestinal (GI) quality standards publication. 16. We recommend that when colonic surveillance is required after previous polypectomy, computed tomography colonography (CTC) is an acceptable alternative if colonoscopy is incomplete or not possible due to the patient’s clinical condition. 17. We recommend that when colonic surveillance is required after curative-intent resection of CRC, CTC should only be used for individuals in whom colonoscopy is contraindicated or not possible due to the patient’s clinical condition. 18. We recommend that when post-polypectomy surveillance is indicated, the radiation risk of CTC is likely to be outweighed by its potential benefits. 19. We do not recommend the use of faecal immunochemical testing for surveillance after resection of premalignant colorectal polyps, as there is insufficient evidence. 20. We do not recommend the use of colon capsule for surveillance after resection of premalignant colorectal polyps, as there is insufficient evidence.

Hereditary non-polyposis colorectal cancer (Lynch Syndrome)

1-3% of all CRC
Autosomal dominant genetic disorder
80% pentrence
Due to germline mutations in a single DNA mismatch repair (MMR) genes (micro-setalite instability).
MMR genes: MLH1,MSH2,MSH6,PMS2
Gastrointestinal cancer risk associated with Lynch syndrome is variously reported as around 80% for colorectal cancer and 13 to 20% for gastric cancer.
Evidence indicates that the colorectal cancer risk for males is higher than that for females.
Between 0.3% and 2.4% of all patients with colorectal cancer have a family history criteria of Lynch syndrome.
The proportion of colorectal cancer cases due to mutations in DNA MMR genes is 2 to 3%,

Synchronous tumour: two or more tumours present at the same time
Metachronous tumour:first tuomour is followed by a second one at a later date
both are common
Increase risk of endomerial cancer, ovarian, urinary tract and skin cancer.

Diagnosis:
Difficult as no specific phenotype.
Two main diagnostic guideline in the West to identify patients:

Families with Lynch syndrome should be referred to the regional clinical genetics service or other specialist service to facilitate risk assessment, genetic testing and screening of family members.
(Recommendation grade: C)

Management:
-Large bowel surveillance for Lynch syndrome family members and gene carriers

-Total colonic surveillance (at least biennial) should commence at age 25 years

-Surveillance should continue to age 70 to 75 years or until co-morbidity makes it clinically inappropriate.

full colonoscopy or barium enema remains the best  options available.
Patients who have developed a colorectal malignancy and who come from a Lynch syndrome family, or carry a mutation in an MMR gene, should be counselled and offered a surgical procedure(colon resection) that serves both as cancer control element and prophylaxis to prevent future cancer risk.
(Recommendation grade: C)

-Upper gastrointestinal surveillance for Lynch syndrome family members and/or MMR gene carriers:

In families manifesting gastric cancer as part of the phenotype, biennial upper gastrointestinal endoscopy should be considered.

Surveillance should continue to age 75 or until the causative mutation in that family has been excluded.
(Recommendation grade: C)

Inherited hamartomatous polyposis syndromes

1-Peutz-Jaghers Syndrome PJS

Autosomal dominant with high penetrence

Mucocutaneous pigmentation in 95% of patients

Hamartomaous intestinal polyposis

Mutation of the STK11/LKB1, a serine threonine kinase gene on chromosome 19p, also known as B1(LKB1).

80% of PJS have no detectable mutation
Average age at diagnosis: 23-26

Main symptoms: abdominal pain, GI bleeding or anaemia

Associated with high risk of cancers (colon, stomach, pancreas, breast,..)

Diagnosis:

clinical

-two PJ polyps are detected

-single PJ polyp + perioral pigmentation

-single PJ polyp + family history of PJS

Genetic testing

Feautures of PJS should leed to genetic testing
All first degree relatives should be tested

Management:

-colonoscopy from the age of 25 yrs, every 2 years

-OGD from the age of 25 yrs, every 2 years

-small bowel: MRI, VCE, every 2-4 years

-surveillance for extraintestinal cancer

treatment depends on polyp burden and location

-  few adenomas-----> polypectomy and medical treatment

- multiple polups or clusters---->surgical resection and life long surveillance

- laprotomy for small bowel obstruction

mucocutaneous pigmentation around mouth, nostrils,perianal, genital area, hands and feet.

2-Juvenile polyposis syndrome JPS

Distinctive hamartomas that usually are solitary and located principally in the rectums of children

JPS can be defined by any one of the following criteria:

-More than five juvenile polyps of the colon and rectum

-Juvenile polyps throughout the GI tract

-Any number of juvenile polyps in the GI tract with a family history of juvenile polyps

Typically causes GI bleeding and obstruction

Age of a patient with JPS is 4.5-9.5 yrs

Risk of colon and upper GI ca is increased

JPS manifests autosomal dominant inheritance

Caused by mutations in two genes:
–Approximately 18% of cases will have a germline mutation of MADH4 (SMAD4)
–Another 21% of JPS cases are caused by germline mutations of bone morphogenetic protein receptor 1A (BMPR1A) obstruction.

Age of a patient with JPS is 4.5-9.5 yrs

                                                           Juvenile polyp

Management:

Screening colonoscopy usually begins after 15 yrs of age. Every 2 yrs

OGD from age 25

Polypectomy performed yearly until the patient is polyp free and then every 3 year

Asymptomatic relatives also should be screened by the age of 15yrs

Identification of MADH4/BMPR1A

Colectomy considered if numerous polpys

Question:

This 23-year-old man presented via the rapid access rectal bleeding service. At flexible sigmoidoscopy,this polyp was detected in the sigmoid colon, as shown above. At subsequent colonoscopy, he was found to have five other similar lesions. All of these statements below are accurate, except

1- this polyp required a biopsy at the time of flexible sigmoidoscopy

2- nearly all cases where these polyps are found have a mutation found on molecular genetic testing

3- this polyp does not require endoscopic removal

4- a family history should be taken

5- predictive gene testing of his 4-year-old son is appropriate if a mutation is found on molecular genetic testing.

3-Cowden Disease

 an autosomal dominant condition.

germline mutation of the PTEN gene on chromosome 10q23. 

Oral and cutaneous hamartomas, thyroid, breast and endometrial tumours, autoimmune

thyroiditis, macrocephaly and mental retardation are documented manifestations.

Percentages of colon cancer