Re: Diagnosis of an AutoImuune Disease

[Guest guest]

Hi Melvyn;

One of our newsletter articles discussed auto-antibodies in autoimmune

liver diseases (see page 2 of):

http://www.pscpartners.org/NewsVol-1-7.pdf

This is reprinted below, but without the accompanying Figure:

_______________________

Diagnosis of autoimmune liver diseases often begins with the

observations of elevated liver function tests (alanine aminotransferase

(ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase

(GGT), alkaline phosphatase (ALP)), and sometimes elevated bilirubin in

serum. However, this is not always sufficient for accurate diagnosis.

Often a series of antibody tests are performed to assist in diagnosis

(see adjacent figure). For instance, anti-mitochondrial antibodies

(AMA) (usually directed against the pyruvate dehydrogenase E2 subunit

(anti-PDH E2)) are frequently characteristic of primary biliary

cirrhosis (PBC). Smooth muscle antibodies (SMA) are characteristic of

autoimmune hepatitis (AIH) type 1. Liver/kidney microsomal type 1

(anti-Lkm1) antibodies are characteristic of AIH type 2. Soluble liver

antigen/liver pancreas antigen (anti-SLA/LP) are associated with AIH

type 3. Primary sclerosing cholangitis (PSC) is associated

with atypical p-ANCA antibodies, where p-ANCA stands for perinuclear-

antineutrophil cytoplasmic antibodies. Extractable nuclear antigens

(ENA) and anti-Actin antibodies can help confirm AIH type 1 diagnosis,

and when occurring with atypical p-ANCA, might suggest a PSC/AIH

overlap syndrome. Similarly, AMA antibodies, together with p-ANCA,

might suggest a PBC/AIH overlap syndrome. Absence of most of the

above antibodies might suggest autoimmune cholangitis (AIC). There is

some evidence that AIC is a form of biliary cirrhosis (PBC) without

anti-mitochondrial antibodies (AMA), but it is also speculated that AIC

might be very similar to small duct PSC [a variant of PSC that does not

affect the large ducts].

Where PSC is suspected, based on liver function tests and antibody

profile, imaging of the biliary tree is essential for accurate

diagnosis. Two imaging techniques are now extensively used for this

purpose:

• endoscopic retrograde cholangiopancreatography (ERCP)

• magnetic resonance cholangiopancreatography (MRCP)

In ERCP a flexible tube, or endoscope, is inserted into the upper

gastrointestinal tract (via the mouth and esophagus), and a dye is then

injected into the bile and pancreatic ducts. An X-ray is then taken to

image the bile and pancreatic ducts. In MRCP, no contrast dye is used,

no radiation is involved, and no endoscope is employed. Rather,

patients are simply exposed to a strong magnetic field and the bile

ducts are visualized because the stationary fluid in the bile ducts

produces a higher intensity signal in comparison to the surrounding

tissue. A `beaded' appearance of the bile ducts revealed by these

imaging techniques would strongly suggest PSC.

Terjung B, Spengler U (2005) Role of auto-antibodies for the diagnosis

of chronic cholestatic liver diseases. Clin. Rev. Allergy Immunol. 28:

115-133.

_______________________

One of the most interesting (at least to me!) antibodies in PSC is the

anti-neutrophil cytoplasmic autoantibodies (ANCA) directed against

bactericidal/permeability-increasing protein (BPI):

Schultz H, Weiss J, Carroll SF, Gross WL 2001 The endotoxin-binding

bactericidal/permeability-increasing protein (BPI): a target antigen of

autoantibodies. J. Leukoc. Biol. 69: 505-512.

http://www.ncbi.nlm.nih.gov/pubmed/11310835

BPI is involved in detoxifying lipopolysaccharide (LPS) (also known as

endotoxin). BPI-ANCA may compromise the ability of PSCers to detoxify

lipopolysaccharide, resulting in accumulation of LPS in the liver,

resulting in inflammation and impairment of bile transport by biliary

epithelial cell:

Sasatomi K, Noguchi K, Sakisaka S, Sata M, Tanikawa K 1998 Abnormal

accumulation of endotoxin in biliary epithelial cells in primary

biliary cirrhosis and primary sclerosing cholangitis. J. Hepatol. 29:

409-416.

http://www.ncbi.nlm.nih.gov/pubmed/9764987

The 3 diseases that seem to have the highest levels of BPI-ANCA are

cystic fibrosis, PSC and IBD. It's likely that the lack of CFTR in

cystic fibrosis causes an inability to regulate pH in the small

intestine (CFTR collaborates with an anion exchanger, AE2, to pump

bicarbonate into the small intestine (and bile)). The bicarbonate

excretion is sufficient to make the gut epithelial surface alkaline,

and this allows intestinal alkaline phosphatase to function properly.

In the absence of CFTR (or AE2) then intestinal alkaline phosphatase

can't function (i.e. the pH is too acidic). Because intestinal alkaline

phosphatase is a first line defense against lipopolysaccharide (i.e. it

clips off the phosphate groups from lipopolysaccharide), this could be

the starting point for elevated lipolysaccharide in the gut.

Bates JM, Akerlund J, Mittge E, Guillemin K 2007 Intestinal alkaline

phosphatase detoxifies lipopolysaccharide and prevents inflammation in

zebrafish in response to the gut microbiota. Cell Host Microbe 2: 371-

382.

http://www.ncbi.nlm.nih.gov/pubmed/18078689

Excess lipoplysaccharide in the gut could then cause an increase of gut

permeability, eventually overwhelming the second-line defense (BPI),

causing BPI-ANCA to appear because of formation of excess amounts of

BPI-lipopolysaccharde complexes?

PBCers have defective regulation of AE2:

Melero S, Spirlì C, Zsembery A, Medina JF, Joplin RE, Duner E, Zuin M,

Neuberger JM, Prieto J, Strazzabosco M 2002 Defective regulation of

cholangiocyte Cl-/HCO3(-) and Na+/H+ exchanger activities in primary

biliary cirrhosis. Hepatology 35: 1513-1521.

http://www.ncbi.nlm.nih.gov/pubmed/12029638

PSCers seem to have defective regulation of CFTR:

Pall H, Zielenski J, Jonas MM, Dasilva DA, Potvin KM, Yuan, XW, Huang

Q, Freedman SD 2007 Primary sclerosing cholangitis in childhood is

associated with abnormalities in cystic fibrosis-mediated chloride

channel function. J. Pediatr. 151: 255-259.

http://www.ncbi.nlm.nih.gov/pubmed/17719933

Best regards,

Dave

(father of (22); PSC 07/03; UC 08/03)

> How is an autoimmune disease diagnosed? PSC is an autoimmune disease,

I want to know that how can they diagnose it except PSC Symptoms. by

Factors/ Antibodies/ Functional tests/ or sth else of the attacked

organ? what is that for PSC? It may give me a clue if I know it to be

more determined in the way of my research.