Find information on thousands of medical conditions and prescription drugs.

Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an inherited condition in which numerous polyps form mainly in the epithelium of the large intestine. While these polyps are benign, they may become malignant, predisposing patients to colorectal cancer. more...

Home
Diseases
A
B
C
D
E
F
Fabry's disease
Facioscapulohumeral...
Factor V Leiden mutation
Factor VIII deficiency
Fallot tetralogy
Familial adenomatous...
Familial Mediterranean fever
Familial periodic paralysis
Familial polyposis
Fanconi syndrome
Fanconi's anemia
Farber's disease
Fascioliasis
Fatal familial insomnia
Fatty liver
Febrile seizure
Fibrodysplasia ossificans...
Fibromatosis
Fibrosarcoma
Fibrosis
Fibrous dysplasia
Filariasis
Fissured tongue
Fitz-Hugh-Curtis syndrome
Flesh eating bacteria
Fluorosis
Focal dystonia
Foix-Alajouanine syndrome
Follicular lymphoma
Fountain syndrome
Fragile X syndrome
Fraser syndrome
FRAXA syndrome
Friedreich's ataxia
Frontotemporal dementia
Fructose intolerance
Fructose-1,6-bisphosphatase...
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Y
Z
Medicines

Signs and symptoms

From the age of 16 onward, patients develop hundreds to thousands of polyps. These may bleed, leading to admixture of blood in the stool. If the blood is not visible, it is still possible for the patient to develop anemia due to gradually developing iron deficiency. If malignancy develops, this may present with weight loss, altered bowel habit, or even with metastasis in the liver or elsewhere.

The genetic determinant in familial polyposis may also predispose carriers to other malignancies, e.g. of the duodenum and stomach. Other signs that may point at FAP are pigmented lesions of the retina ("congenital hypertrophy of the retinal pigment"), jaw cysts, sebaceous cysts, and osteomata (benign bone tumors). The combination of polyposis, osteomas, fibromas and sebaceous cysts is termed Gardner syndrome (with or without abnormal scarring).

Diagnosis and treatment

In patients with a strong family of colorectal cancer and symptoms suggestive of polyposis, colonoscopy is indicated, with biopsy of a number of polyps (especially of those that appear dysplastic). In severe cases, a full or partial colectomy is required.

Blood tests (liver enzymes) and ultrasound of the abdomen are often performed to rule out metastasis to the liver.

Genetic testing provides the ultimate diagnosis in 95%; genetic counseling is usually needed in families where FAP has been diagnosed. Testing may also aid in the diagnosis of borderline cases in families that are otherwise known to have the FAP mutation.

Pathophysiology

FAP is due to mutations in the APC gene, which is located on the fifth chromosome (5q21-q22), or in the MUTYH gene located on chromosome 1 (p34.3-p32.1).

APC is a tumour suppressor gene, acting as a "gatekeeper" to prevent development of tumours. Mutation of APC also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer.

Although the polyps are inherently benign, the first step of the two-hit hypothesis has already taken place: the inherited APC mutation. Often, the remaining "normal" allele is mutated or deleted, accelerating generation of polyps. Further mutations (e.g. in p53 or KRAS) to APC-mutated cells are much more likely to lead to cancer than they would in non-mutated epithelial cells.

The normal function of the APC gene product is still being investigated; it is present both the cell nucleus and the membrane. The canonical tumor-suppressor function of Apc is suppression of the oncogenic protein beta-catenin. However, other tumor-suppressor functions of Apc may be related to cell adherence and cytoskeleton organization.

Read more at Wikipedia.org


[List your site here Free!]


Celecoxib Approved for Familial Adenomatous Polyposis - Brief Article - Statistical Data Included
From Family Pratice News, 1/15/00 by Elizabeth Mechcatie

BETHESDA, MD. -- The arthritis drug celecoxib has been approved as an adjunct to the standard treatment of familial adenomatous polyposis, an approval based on data that showed the drug reduced the number of intestinal polyps in this population.

This indication was approved nine days after the Food and Drug Administration's Oncologic Drugs Advisory Committee recommended that celecoxib be approved for use in people with familial adenomatous polyposis (FAP), an uncommon but devastating genetic disease that affects about 1 in every 10,000 people.

The specific indication proposed by G.D. Searle & Co., which already markets celecoxib as Celebrex for osteoarthritis and rheumatoid arthritis, is for "the reduction and regression of adenomatous colorectal polyps" in patients with FAP.

The vote and approval was based on a 6-month study of such patients that showed a significant reduction in the number of polyps and overall polyp burden in those treated with 400 mg of celecoxib twice a day, compared with placebo.

Celecoxib is one of the cyclooxygenase-2 (COX-2) inhibitors. These agents inhibit production of COX-2, which causes inflammation and pain, but not COX- 1, which produces protective gastric prostaglandins. Traditional NSAIDs inhibit both COX-1 and COX-2.

COX-2, expressed at high levels by colon cancer cells and colon cancer metastases, is not usually expressed by normal colonic cells, according to Searle.

Celecoxib is not being proposed as a replacement for standard FAP therapy, which includes endoscopic surveillance and surgery. If left untreated, people with FAP develop colon cancer at a mean age of 39; nearly 100% develop colon cancer at some point. By age 21, 80% of people with FAP have had colorectal surgery.

There are no data past 6 months on celecoxib's effects on colorectal polyps in such patients, so it is unclear whether use of the drug will reduce colon cancer risk and the need for surgery. Searle is planning a study of celecoxib in 12- to 19-year-olds with a genetic FAP diagnosis who have not yet shown signs of the disease; the primary endpoint will be the proportion who reach age 21 before needing surgery.

Most members of the FDA panel agreed that a reduction in colorectal polyp counts, a surrogate endpoint, was "reasonably likely" to predict a clinical benefit, assuming that all other aspects of patient care were unaltered. Clinical benefits for these patients would include a reduced colorectal cancer rate and a reduction or delay in the need for colorectal surgery.

For a serious or life-threatening disease that lacks adequate therapy the FDA can approve a drug on the basis of an effect on a surrogate endpoint that is "reasonably likely" to predict clinical benefit, but the manufacturer must study such outcomes in postmarketing trials.

Panel member Dr. David P. Kelsen, chief of the GI oncology service at Memorial Sloan-Kettering Cancer Center, New York, said that the data convinced him that the drug reduces polyp count, but that follow-up studies on whether major surgical procedures can be delayed in a young population are "crucial." If treatment prevents the polyp development and reduces or delays the need for surgical procedures, "that would be a major impact," he said.

Searle conducted the 6-month study in collaboration with the National Cancer Institute's Division of Cancer Prevention. A large body of epidemiologic data shows that NSAID use is associated with reduced rates of adenomas, colon cancer, and colon cancer deaths, but side effects have limited NSAID use in this area. If they can tolerate it, most patients with FAP take sulindac, which has been shown to reduce polyp counts.

The randomized, double-blind study which included 83 patients with FAP who had at least five colorectal polyps measuring 2 mm or more, was conducted at the University of Texas M.D. Anderson Cancer Center, Houston, and at St. Mark's Hospital, London. Subjects abstained from using NSAIDs for the previous 6 months.

At the end of 6 months, there was a mean 28% reduction in endoscopic colorectal polyp count in focal areas in the 30 patients who received celecoxib 400 mg b.i.d., compared with a 14.5% reduction in the 33 treated with 100mg b.i.d. and a 4.5% reduction in those on placebo. The polyp burden, a secondary endpoint, was reduced by 10% in those on the highest dose, compared with 14.6% and nearly 5% in those on the 100-mg dose and placebo, respectively

Diarrhea and dyspepsia were the most common side effects of celecoxib. One patient on the 400-mg dose had a severe allergic reaction that was "probably" related to the drug, according to Searle.

Currently there are no safety data on patients taking celecoxib 400 mg b.i.d. past 6 months, according to the FDA.

Searle will be doing studies of celecoxib in patients with other diseases in which affected tissues express high levels of COX-2, including sporadic adenomatous polyposis, Barrett's esophagus, actinic keratoses, and superficial bladder cancer.

COPYRIGHT 2000 International Medical News Group
COPYRIGHT 2001 Gale Group

Return to Familial adenomatous polyposis
Home Contact Resources Exchange Links ebay