Re: update and interesting theory

May 18, 2006

> My head is still reeling with the thought that I could have been

> misdiagnosed for eight years, had a liver transplant, and then learn

> a new label for my problems.

I'd think of it as a new understanding for the cause of your problems.

No matter whether you call it CF or PSC your symptoms required a liver

transplant. I'm not up to date on CF, but I don't think there's been

any breakthrough treatment that could have prevented your liver failure.

Steve Freedman and others have found that some CF variants are

elevated in PSC patients. CF is recessive- there are a lot more

carriers with a single mutation than there are CF patients, who have

two mutations. There are also a lot of reduced function mutations,

that leave the CFTR channel working, but not well (in genetic terms, a

hypomorphic allele). There's evidence that the CFTR mutations

protected against typhoid fever (Pier GB, Grout M, Zaidi T, Meluleni

G, Mueschenborn SS, Banting G, Ratcliff R, MJ, Colledge WH.

Salmonella typhi uses CFTR to enter intestinal epithelial cells.

Nature. 1998 May 7;393(6680):79-82). This would be similar to the

beneficial effect of a single sickle-cell gene in protecting from Malaria.

CFTR knockout mice, experimentally induced to develop colitis, also

develop PSC. This is the basis for his ongoing clinical trial for DHA

(a fish oil omega 3 fatty acid) in treating PSC. The PSC improved a

lot in the mice treated with DHA.

Here are some refs- I'm sure will give you more

Martha (MA)

Am J Physiol Gastrointest Liver Physiol. 2004 Aug;287(2):G491-6. Epub

2004 Apr 2.

Induction of colitis in cftr-/- mice results in bile duct injury.

Blanco PG, Zaman MM, Junaidi O, Sheth S, Yantiss RK, Nasser IA,

Freedman SD.

Beth Israel Deaconess Medical Center, 330 Brookline Ave., Dana

501, Boston, MA 02215, USA.

It is unknown why some patients with inflammatory bowel disease

develop primary sclerosing cholangitis. We have recently shown that

patients with primary sclerosing cholangitis have an increased

prevalence of mutations in the gene responsible for cystic fibrosis

(CFTR) compared with individuals with inflammatory bowel disease

alone. Our aim was to examine whether induction of colitis by oral

dextran leads to bile duct injury in mice heterozygous or homozygous

for mutations in CFTR. The effect of oral administration of

docosahexaenoic acid to correct a fatty acid imbalance associated with

cystic fibrosis was also examined to determine whether this would

prevent bile duct inflammation. Wild-type mice and mice heterozygous

and homozygous for CFTR mutations were given dextran orally for 14

days to induce colitis. Bile duct injury was quantitated by blinded

histological scoring and measurement of serum alkaline phosphatase

activity. The effect of pretreatment with docosahexaenoic acid for 7

days was examined. Treatment of mice with 100 mg dextran/day for 9

days followed by 85 mg/day for 5 days resulted in a significant

increase in bile duct injury as determined by histological scoring in

homozygous cystic fibrosis mice compared with wild-type mice (P =

0.005). The bile duct injury seen in cystic fibrosis mice was

reflected in a threefold increase in serum alkaline phosphatase (P =

0.0006). Pretreatment with oral docosahexaenoic acid decreased both

histological evidence of bile duct injury and serum alkaline

phosphatase levels. In the setting of colitis, loss of CFTR function

leads to bile duct injury.

Hum Genet. 2003 Aug;113(3):286-92. Epub 2003 Jun 3.

Increased prevalence of CFTR mutations and variants and decreased

chloride secretion in primary sclerosing cholangitis.

Sheth S, Shea JC, Bishop MD, Chopra S, Regan MM, Malmberg E,

C, Ricci R, Tsui LC, Durie PR, Zielenski J, Freedman SD.

Department of Medicine, Beth Israel Deaconess Medical

Center/Harvard Medical School, Dana 532, 330 Brookline Avenue, Boston,

MA 02215, USA.

Primary sclerosing cholangitis (PSC) and cystic fibrosis (CF) are

both slowly progressive cholestatic liver diseases characterized by

fibro-obliterative inflammation of the biliary tract. We hypothesized

that dysfunction of the CF gene product, cystic fibrosis transmembrane

conductance regulator (CFTR), may explain why a subset of patients

with inflammatory bowel disease develop PSC. We prospectively

evaluated CFTR genotype and phenotype in patients with PSC ( n=19)

compared with patients with inflammatory bowel disease and no liver

disease ( n=18), primary biliary cirrhosis ( n=17), CF ( n=81), and

healthy controls ( n=51). Genetic analysis of the CFTR gene in PSC

patients compared with disease controls (primary biliary cirrhosis and

inflammatory bowel disease) demonstrated a significantly increased

number of mutations/variants in the PSC group (37% vs 8.6% of disease

controls, P=0.02). None of the PSC patients carried two

mutations/variants. Of PSC patients, 89% carried the

1540G-variant-containing genotypes (resulting in decreased functional

CFTR) compared with 57% of disease controls ( P=0.03). Only one of 19

PSC patients had neither a CFTR mutation nor the 1540G variant. CFTR

chloride channel function assessed by nasal potential difference

testing demonstrated a reduced median isoproterenol response of 14 mV

in PSC patients compared with 19 mV in disease controls ( P=0.04) and

21 mV in healthy controls ( P=0.003). These data indicate that there

is an increased prevalence of CFTR abnormalities in PSC as

demonstrated by molecular and functional analyses and that these

abnormalities may contribute to the development of PSC in a subset of

patients with inflammatory bowel disease.

May 18, 2006