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Pbc suspected but no urso if normal liver biochemistry

During my consultation with a rheumatologist for my knee and finger arthritis my blood tests revealed antibodies against ANA 1:1240 with MND positivity in immunofluorescence as well as the positivity of 3 very highly specific pbc markers i.e. tantibodies against namely M2-3E, Sp-100 and PML but AMA negative and normal liver enzymes namely Alk. Phosphatase, GGT, AST, ALT and normal bilirubin and normal prothrombin time. Hence suspected PBC and started urso 500 mg daily to be gradually increased over 2 months to 1000 mg. But on being referred to Gastroenterologist for liver biopsy for confirmation of diagnosis and staging, he suggested stopping of urso and no liver biopsy with just checking on liver enzymes once every two years as according to him normal liver biochemistry means no active disease. But as i have been reading liver biochemistry gets altered only in late stages and urso is most effective when started early in disease. So should i stop taking urso especially without ruling out active disease with a liver biopsy. Please suggest regarding liver biopsy too besides continuing urso and further management. Thank you for your guidance.

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Hello Mmetha.

I thought you had to be AMA positive for PBC diagnosis. ANA tends to mean something else but I don't know what.

I had itching and fatigue back in early 2010 and was found to have abnormal liver function test (LFTs). By the end of the year I was diagnosed with PBC due to the consultant checking antibodies. He said I had a high titre of AMAs (the anti-mitochondria antibodies) and a negative for ANA. I was also found to have abnormal GGT in the blood test which is one usually taken with anyone with a liver disorder. With these 3 factors I got a diagnosis. In the UK a biopsy on this basis for PBC diagnosis isn't normally undertaken unless the doctor has any doubt as to what a diagnosis should be.

I started urso in Dec 2010 and still have abnormal LFTs and also GGT. Urso had made a big difference though, fatigue long since left me, I still itch but it is generally confined to nights.

Urso can also be taken with other liver problems as I have discovered (a relative that isn't blood related to me was diagnosed with PSC another liver disorder 2yrs ago now and she recently said that she had been started on urso).

There seems to be some disagreements between doctors regarding urso and when to take with PBC. Seems that some who have normal LFTs with a PBC diagnosis don't take it but are monitored for any changes.

From the last-but-one Bear Facts magazine from the PBC Foundation there were 2 articles, one on urso and another on itching. It seems that the general consensus is that once a patient starts on urso for PBC it is continued regardless of the bloods. Some return to normal on urso and others may never do so.

A liver biopsy apparently can show PBC due to the cell changes but there seems a bit of confliction between staging as the liver is a large organ and what is taken for biopsy might not be the full picture of the liver.

When I was going through various blood checks in 2010 one was to check whether the abnormal LFTs were due to a bone disorder or liver disorder. Certain medications too can alter the LFTs.

I cannot say if you have PBC or not, only your doctor can say this. But it does seem normal for someone with normal liver function tests and other blood checks that can become abnormal in something like PBC to have blood checks at certain intervals just to keep an eye on them. I have bloods done every 6 months now, used to be every 3 in the earlier days.

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Hi Peridot, just to clarify something you wrote, there are about 5-10% of PBCers who are AMA neg. See link below:


Hope you're keeping well.

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Hello DianneS.

Yes I am keeping well.

In my case as in the UK one can be diagnosed with PBC if they have symptons like the 2 common ones I had back in 2010 (itching and fatigue), abnormal or elevated LFTs and usually GGT plus if positive of what I believe a certain measure (mine was said to be 'a high titre') of the AMAs then you can be diagnosed with PBC. I know back in 2010 if I'd have shown a negative for AMAs expect I'd have been asked to have a biopsy. I know I had ANA and AMA done same time and the ANAs in my case was negative.

I think what I was trying to get my head around with my reply was that was there some confusion in the poster between ANAs and AMAs. I know it is apparently found that as you have stated and what I believe I have read some place before, seems that most patients diagnosed with PBC do have AMAs. Like everything though seems there are exceptions to the rules... know that with this PBC lark as I call it, there seems to be a lot of contradictions and seems that the bloods can be one of them.


Good to hear you'er doing well.

I was pretty sure you would have read, or known, about the statistics on AMA pos. and AMA neg., but thought just in case you hadn't, or any other person reading these posts, I would provide the link.

I can't be sure about being ANA positive when I was first diagnosed, but I am now. The Rheumatologist I was sent to 5 years ago ordered a number of blood tests, ANA being one of them, it came back positive - I have asked my GP (who I have been seeing for over 30 years) if I had been ANA pos. when first diagnosed with PBC 27 years ago, but he doesn't know, so I don't know if it was a later 'add-on' or not.


Hello again DianneS.

Out of interest do you know what an ANA positive test means. Does it at all have something to do with bone health?

I know we can have abnormal LFTs if there is a bone problem. Back in 2010 the doctor determined early on that I had a problem with the liver area as opposed to the bones. He said he had done a test to determine if the abnormal LFTs were due to bone or liver.

I know I often read on this site that someone has tested positive for ANAs and/or AMAs but not sure what the ANAs mean. I know it stands for anti-nuclear which are other cells but don't know much more. I think due to me having a negative for ANAs I haven't take notice.

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I'll place a link below, from the Mayo Clinic website, which explains ANA. I have read through the article and it doesn't mention 'bone health' so I would hazard a guess that ANA probably doesn't indicate bone issues.


My Rheumatologist said that my positive ANA could just be indicating I have PBC - an autoimmune condition.


Hello DianneS.

Thanks for the link, just had a look at it and another on another site (one to do with rheumatology). Seems that someone with a positive ANA results could be an indicator they have some auto-immune problem but also does state that certain medications and even healthy people can have a positive reading.

I feel a bit puzzled now but the ANAs don't actually concern me as I did have a negative result so won't think about that unless I have to.

Thanks for trying to clarify.

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Hello Peridot.

Thanks for your prompt reply and guidance. Although I am AMA (antimitochondrial antibodies) negative I am positive for M2-3E (mitochondrial antibodies againgst 3 epitopes) which is equally specific of pbc as AMA if not more. And as DianneS also wrote to you and you too know the same I too have read that 95% of pbc test positve for AMA but 5% are AMA negative. Also there are controversies between doctors as to the diagnosis of pbc, the most accepted seems to be when at least 2 of the following 3 are positive or suggestive of pbc -

1. AMA positive

2. Raised LFT especially Alk Phosphatase and GGT

3. Liver biopsy

You have it right that liver is a big organ hence biopsy might show normal areas despite pbc pathology in another portion at the same time.

Taking the above into consideration Although ama negative i am M2-3E positive with perfect blood biochemistry so only liver biopsy can confirm or refute the diagnosis of pbc. Also Sp100 and pml are also highly significant for pbc just as is the MND fluorescence pattern. But my consultants are are not advising liver biopsy still because they are only taking the perfect blood biochemistry into consideration while saying that at the moment it is not active disease and hence no urso to be started too.

I wonder if anyone else is aware of these other tests M2-3E , sp100 , pml, mnd fluorescence pattern in regards to pbc.

As regards to ANA (anti nuclear antibodies) they are non specific for pbc and can be an indication of arthritis or other connective tissue disorders. As is my case i have knee and finger joint pains and stiffness for which i consulted a rheumatologist which resulted in the pbc serology during the blood tests.

I do have fatigue as a symptom which i had not given much thought and had attributed my fatigue to being the mother of a one year old. itching not troublesome at all maybe a bit sometimes in the night. Frankly i had not thought of these 2 symptoms much until recently when i was suspected pbc.

Urso helps most in improving life span when started early in disease. Liver biochemistry gets altered only in late stages as liver has a great capacity to regenerate so maintaining petfect blood biochemistry until late stages when urso might not be so effective compared to when started early.

I eagerly await others experience and opinion in this too.


Hello again Mmehta.

I am not aware of any other certain tests re PBC as the ones you have mentioned.

In the UK all I know is that if someone has symptons (itching seems to be the common one) and the liver function test is undertaken and found to be abnormal (or elevated as the other terminology goes) then once established that he/she has a liver disorder it seems that an antibodies seems the next step. I had the 3 criteria of 2 symptons, abnormal LFTs and abnormal GGT plus was found to be positive for AMAs and was diagnosed like this. I had no biopsy as the consultant was in no doubt to give diagnosis.

I know when I received his letter as a copy that he sent to my GP to ask him to inform me I needed to start taking urso and that I had PBC, he just stated I had 'a high titre' of the antibodies AMA and that I had a negative for ANA. If there were additional tests undertaken then I am not aware nor if there are certain types of AMAs either.

As I understand it once you have been informed you have PBC then you have PBC regardless of the status. For some it can remain quite dormant it seems and it never really being known with continued nromal LFTs, others it isn't so. I was found to have PBC due to itching but had I not have itched I might never have known I had PBC. The consultant (an hepatologist) who I saw, he reckoned that I started with PBC 'a few years' prior to itching. Some are found due to routine LFTs being taken for other things. I know I did once have an LFT taken several years prior to being diagnosed as sometimes it is the norm if you are going to take iron tablets (I have had a few courses of iron tablets very short-term for mild anaemia) and no-one said anything about it being abnormal.


I would talk to the PBC Foundation people (there is a link to their website at the top of this page, where you will find phone numbers and email address to contact their advisors). It may help to talk to the Liver Trust people too, about other possible liver conditions

I just do not know enough about other liver conditions, to comment, given the results you mention, or indeed, the other markers for PBC you cite.

My understanding is, that to diagnose PBC you need to test +ve for AMAs, and to have abnormal liver function tests, typical of PBC for 6 months or more. If there is doubt, about PBC, then a biopsy is usually considered necessary.

I don't know if you are in the UK, but it is typical here to have the liver enzymes checked at least annually, and I know my GP does checks at other times if I have any worrying symptoms - and as I only have AMAs, and have perfect bloods and no symptoms, I am not diagnosed as having PBC (that would be contrary to UK, US, and Euro medical diagnostic guidelines). The consultant I saw said he absolutely would not give me Urso, but then I have had AMAs for over 23 years now, with no signs of PBC and nothing in my medical history or family history to suggest I'm at risk.

I wonder if it would help to see a liver specialist, rather than a gastroenterologist: Also, perhaps see one of the leading PBC specialists. I'm sure people on here can 'private message' you with suggestions of who to see, if you say where you live.

Try not to worry: talk to the people who know, and take charge of your condition, and treatment, while otherwise looking after yourself and doing things you enjoy. Stress is one of the worst things for any autoimmune condition, so treat yourself.


Hi GrittyReads, I've just read through the above 'link' I have posted, and think you may be interested in the "Discussion" section, particularly the last couple of sentences.


Hi DianneS,

Thanks for that.

I think I've got it - may even have read it, but hadn't noticed the last paragraph.

I was tested for almost anything and everything - autoimmune, etc - under the sun, with my 're-diagnosis' of AMA reactivity 8 years ago. I'll mention it to my GP next time I see her, but I am checked annually - in fact, more often ... as they check every time anything happens with me.

However, it is an old-ish paper, so I'd be interested in more up-to-date stuff. I did start searching around, after I'd looked at this, but then I came across some research endorsed by my consultant - he is one of the leaders in the field, and is obviously into AIH as well as PBC. I know he's not too worried about me, and he knows I'm being carefully monitored, so apart from continuing to go to my GP if I'm ever wobbly, I'm not going to worry.

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Ooops, posted that without signing off...

you take care, and thanks again.


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Thanks GrittyReads for your helpful and quick response.

As you mentioned in doubtful suspected pbc cases a liver biopsy is usually considered necessary. But my consultant is not in favour of it because of my perfect bloods too.

Good to know that u have perfect blood tests and despite AMA positivity for over 23 years no pbc and hence not started on urso. May i ask if you had a liver biopsy that ruled out pbc.

Please read my post to Peridot where i have elaborated on AMA negative but M2-3E positive pbc to help me avoid repetition but consideration of other specific tests. I would value your opinion on the same.

Don't the people from pbc foundation and liver trust follow the posts here. I would like to seek their advice in the matter as you suggested as also consulting a hepatologist.

As for location, its near Chemnitz in Germany or Delhi in India if anybody can suggest a pbc specialist in either location.


Hi Mmehta,

No, I have not had a biopsy. In the UK they don't seem so keen to do them, unless there is great concern. I think if I had any symptoms of PBC, but my lfts still stayed normal it might be considered: as well as all other possible liver/autoimmune conditions being ruled out (yet again).

As I said earlier, I don't know about the 3 markers you mention: M2: 3E sp- 100, & pml. I just know I have the M2 sub-type of AMA, so maybe the markers you mention are the sub-names of different AMA sub-types. I believe some of the sub-types of AMA are specific for other autoimmune conditions, rather than for PBC.

I do have lots of Research Papers on PBC, that I've copied, or they have been sent by others on here who are in a similar situation to myself - but I don't always read all of all of them! Particularly since I saw a new-to-me consultant, who is one of the leading PBC experts, I have been trying to step back from worrying about it.

He said I don't have PBC , and I may never get it, and if I do it would not be for a while, and would be very mild and slow ... so I'm just trying to get on with having a full and happy life. It's also very difficult to keep going on about new concerns, when you have got GPs (who you generally like and trust) almost talking to you in capital letters, saying:

'But you haven't got PBC, stop worrying and get on with your life!" Yet part of me sometimes thinks: 'can I have a biopsy, please ... just to be certain?'

NB The advisors at the PBC Foundation do seem to look at the posts, and often mail people who have particular concerns, but I don't think they monitor everything, nor do they have a full-time, round the clock presence - and it is a Bank Holiday weekend here in the UK!! The emphasis is always on asking posters to get in touch with the PBC foundations - that's why I always try to put that advice in my answers to people.

They are also a charity, and a relatively small one, as PBC is so uncommon.

There are different sites for different conditions, here on 'Health Unlocked' and some of the sites and advisors are more particular than others - I think that may reflect the money the organisations have to put into funding the sites.

Some sites respond to all, quickly, and some are also very particular about posters not mentioning: Medics, hospitals, Centres, etc by name, as that is not considered ethical. People are advised to 'Private Message' each other if they want to share info about a consultant they recommend.

As you are not UK based (most on here seem to be from the UK or the US, although folk from many other countries do post on here) I think it would be best to send in a new post, asking advice from people who are from the areas which are useful to you. Ask them to 'private message' you with any Medics that they can recommend in your two areas. Also, do this mid-week, as I've noticed that not many people check in here at the weekends.

NB the British Liver Trust is a separate body, and has a separate site on here. I look on there occasionally, but I'm not sure if they check on posts more or less than the PBC Advisors.

Hope this helps, a little.

Take care,



Hello Gritty.

Thanks again for your prompt reply.

M2-3E is more advanced than AMA that is done in AMA negative pbc suspect ed and is the same M2 type AMA that you mention. This above test is the one described in the article link posted by DianneS in one of the above posts. sp100 and pml are not sub types of AMA but separate markers that if present may indicate a poor prognosis in pbc.

I would like to share this with you that 1% of normal population is AMA positive who never go on to develop pbc. Its good that despite your being AMA positive for over 23 years your lfts are normal so i would accept your doctor's words that you have no pbc still and if at all it ever develops it will be very slow. I pray for you and hope u are in that 1% subset of population and never develop pbc. In my opinion too u dont need a liver biopsy.

I hope to be in that 1% population too, but unfortunately in my case the other specific markers are also present hence the worry and apprehension about my doctor not ruling it out with a biopsy but just relying on normal lfts and just waiting for their derangement to say yes now u can start urso.

By the way AIH has for the moment been ruled out for me. Its markers were negative for me.

I will post again mid week as you suggested.

Take care and yes with a positive note we should continue to live happily as stress is not good for any autoimmune disease.


Hello again Mmehta.

Thinking more about certain postings, it would be good to have some medical professional to have say another area on here with just some information on PBC for posters to read. I don't necessarily mean for a professional to get into any discussions on here as everyone has varying symptons plus blood results and without personal records probably not something one is able to fully respond to.

But it would be good to occasional have a posting to query something that someone might have posted to or replied for better understanding. I'd start with your mention of the other things you have mentioned as in M2...


Okay Angela, I'm not sure if you are querying what M2 is, or just thinking it might be good to have a 'professional' giving information - anyway, I decided to search around for the information - I wasn't sure what the M2 was either - here's a link to the Mayo Clinic (again) which discusses M2.



Hello Peridot.

Your suggestion of a professional giving information is appealing.

The link that DianneS has posted for M2 gives in short that it is a component of mitochondria against which the auto antibodies are directed specifically in pbc. Hence the name AMA M2. The same article also indicates 3 more specific areas in this M2 component that's exactly M2:3E. In other words it is same or rather even beyond AMA M2 in its specificity for pbc.


MMehta, I know I'm late to the party here, but I'd like to chime in. Gritty and others have, in many posts, listed the diagnostic criteria for PBC, which are 2 of 3 of positive AMA, choleastic liver tests (i.e. elevated ALP), and positive histologic or biopsy findings. Based on what you wrote, you have 0 of the 3. Correct?


Hello Kevin733.

Late or early shouldn't be any concern. From my side you are welcome to join. Just to avoid repetition though I'd suggest reading all older posts.

The 2 out of the 3 you mentioned as criteria for pbc diagnosis is known to me and i mentioned it in a post of mine. Liver biopsy as of yet has not been given as an option for me. In another post i have mentioned that M2:3E is same as AMA M2 or even beyond in its high specificity for pbc and even though i am negative for AMA i m positive for M2:3E.

So out of the 3 diagnostic criteria i have 1 positive 1 negative and 3rd still not done which could turn out positive if done. Plus i have other pbc specific markers namely sp100, pml and MND Fluorescence pattern. The occurrence of all together cannot be a mere coincidence..... making the probability of my having pbc even higher.

It appears i m the only one who has had these other tests for pbc . I wonder if anyone else has had them done during their pbc diagnosis work up or even heard of them.


Hello Kevin733.

Yes apparently here in the UK as far as I know from my own experience of being diagnosed with PBC Dec 2010, I had 3 specifics, the symptons I started with - itching and fatigue - plus abnormal or elevated blood work that was slowly climbing each repeat blood and then I was found to have anti-mitonchdria antibodies in what the consultant just put in his letter I got is 'high titre' and all this gave diagnosis PBC.

I have noticed that on clinical trials that there has to be specific diagnostics of PBC and then 2 out of 3 findings to be considered for a candidate.


Hi MMehta,

Thanks. I did read the posts above. But isn't M2 a type of AMA? (The second type discovered, in fact, which is how it got its name)? So being positive for the specific anti-M2-3E surely means also being positive for the more general term AMA, right? Or am I missing something? In the link below, the anti-M2 3E ELISA is characterized as a way of detecting AMA.

This means, as has been noted above, that you're in the same situation as me, Gritty, and many others in the AMA-only crowd. To answer your original question: If your ALP and IGM are both normal, and if your doctor is okay with it, I would stop Urso, with liver enzyme re-tests every six months. If either one of them increase, or if you develop symptoms, I would go back on it. A biopsy doesn't seem necessary. In these regards, I agree with your doctor. AMA, even the highly specific kind you were tested for, is not a "slam dunk" for PBC in the absence of other indicators.


Sorry, here's the link:



Hi Kevin733.

I am so happy to read this reply of yours. Now I know someone who's heard of this M2:3E being more specific than general AMA M2. You are on the right track and your article link clears the confusion on the above 2 markers and that the presence of any one is equivalent to AMA positive.

In your reply you've mentioned my being in the same boat as you and Gritty. By that do u mean that you too are just AMA positive but other blood biochemistry is perfectly normal. May I also ask have you had liver biopsy and diagnosed with pbc or is it like me suspected at the moment.

I'd add again for symptoms I have fatigue since last 6 months and itching for last 1 month. Serious hairfall for an year now and dryness especially mouth for quite sometime. But i had not given credit to any of my symptoms thinking them to be due to my being the mother of a one year old baby.

Also would like to know more about the other markers that are positive in me, if you have info on them.


Hi Mmehta,

Yes, by "in the same boat as me and Gritty" I mean being AMA-positive (which you are, because M2:3E is a type of AMA) but everything else otherwise normall. This means not just perfect LFTs, but also normal blood biochemistry (including enzyme levels) as no symptoms.

Based on the symptoms you mention, PBC is more likely than it would otherwise be. Mouth dryness in particular is a hallmark of autoimmune disease. H The combination of the symptoms you mention with AMA positivity, and being female, is strongly suggestive of PBC, even if you don't meet the diagnostic criteria. Have you, by chance, been diagnosed with any other (comorbid) autoimmune diseases, such as Shogren's Syndrome?



Hi Kevin733,

Just out of curiosity, and correct me if I'm wrong, but it seems like I've read that your AMA titer was in the 30's, I've read that AMA under 1:40 can often be negative on retest. I know that anything over 25 is considered positive and titer doesn't correlate with severity or prognosis, but I've read about the 1:40 in many resources and was curious if you've ever had your AMA retested. Also, you seem very well read in this subject that I would like your opinion on an AMA question. When I asked my Dr.about the AMA-M2 positivity in future development he mentioned the .5% false positive. He also said that a test that they used to use had a more definitive probability of future development of the disease. So, I wondered if he meant the general AMA test. I did find this and found it interesting ncbi.nlm.nih.gov/pubmed/245... Any thoughts?


Hi Jean,

My AMA level was 27.1 units, and my doctors refuse to re-test. The units of the test were units, rather than the titer. I don't know the titer that my result corresponds to, but 27.1 units isn't the same as a titer of 27:1. My understanding is that, roughly speaking, 40:1 corresponds to either 20 or 25 units, so that at 27.1 units, I am over 40:1.

I haven't heard of the 0.5% false positive result you mention, but it wouldn't surprise me. Certainly, more often than that, the result switches from positive to negative. Doctors treat those with consistently positive tests and those whose tests fluctuate between positive and negative identically.

I'm familiar with the article above and, in fact, have corresponded with the lead author. He considered ethnic differences in his study, and I asked whether he considered gender differences as well. He stated that he did not, but concurred that his next analysis should. In our string of emails, it was noted that the disease is 9 times more common in women, but at least one study found AMA positivity to be roughly 2 times more common in men. From this it follows that AMA is approximately 18 times more predictive of PBC in women than men. One theory is that hormonal differences play a role in both the progression of AMA to PBC in women, and the increased prevalence of itching as a symptom in women. He promised to keep me posted on his future research in this area.

That said, AMA positivity, even in women, is not a slam dunk for PBC, in the absence of other indicators. As Gritty has noted, AMA occurs in at least 0.5% (1 in 200) of the healthy population and PBC affects, at most, 1 in 3000 people. So there are obviously many AMA-positive people who will never go on to develop PBC, some of whom are women.

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Hi Kevin,

I knew I would learn from you. Thank you for your response. Actually, I wondered why my number was listed as 68 not 1:68, so I went and pulled out my labs and mine is listed in units too. My Dr. tested it again after I asked him to, as I was hoping it was a fluke and it was relatively the same the second time around with the AMA-M2 at 69.7. He's been pretty reasonable about doing tests that Ive asked him for. I guess when I looked at it the reference range it seemed similar to what I thought the titer ranges were 0-20 neg, 20.1-24.9 equivocal and positive >24.9. Even more confusing is the ranges listed for AMA units that I found online and they're not even close to what is listed on my labs.

Reference Values

Negative: <0.1 Units

Borderline: 0.1-0.3 Units

Weakly positive: 0.4-0.9 Units

Positive: > or =1.0 Units

Reference values apply to

The .5% false positive that I referred to was probably the .5% AMA positivity in general population that you mentioned. My follow-up with the liver Dr. after the biopsy (brief as it was) I rattled off a few questions that I could think of at the time and one was what are the chances that I could still develop PBC or could this be a false positive. He mumbled the .5% something or another as he was opening up the door to end our session. I'm often more confused the more I read. Does the AMA-M2 positivity count in that .5% general population range or is it the more comprehensive AMA, which consists of M2-M9 and I know several of those are seen in other autoimmune disorders. How much of that .5% are titers 1:40 or above and how many of those are in between 1:25-1:40, which I'm assuming anything over 1:25 is positive? Why are some Hepa Dr.'s diagnosing their patients on AMA positivity alone? I bought a digital chapter out of a liver manual about PBC and it states this: "Asymptomatic patients in a rheumatology clinic with AMA titers of 1:40 or greater or AMA levels greater than 0.1unit and normal liver biochemistry values have been followed for up to 30yrs and the likelihood that these individuals will eventually develop clinically evident PBC is very high-- at the end of follow up, 80% of these patients will have definite PBC, and an additional 14% will have probable PBC. Nevertheless, in the general population, in which up to .5% of individuals can test positive for AMA, PBC will actually develop in fewer than 10%. Perhaps healthy individuals found to have AMA positivity should undergo annual evaluation of serum liver biochemistry values, although no specific guidelines currently exist."

This to me is so contradictory and I'm not sure if I understand it. At one point, I find a report that seems to say AMA positivity is virtually diagnostic of PBC and then you read that 0.5 % of the general population have positive AMA. Anyway, sorry to hear that your Drs won't retest your AMA, even if it were not to change I would still want to know. Stay well!


Hi Jean,

The AMA reference ranges you cite from online (e.g. Mayo Clinic) clearly use a different scale. The standard US scale is the one you cited above that.

I concur that, in the general population, at least 0.5% will test as AMA-positive. These are not "false positives," they are legitimate positives. It would become a false positive, presumably, if such a person were diagnosed were diagnosed with PBC based on AMA alone, but was ultimately shown not to have it.

The 0.5% figure applies to AMA positivity generally, and is not specific to the M2 subtype. However, the M2 subtype is by far the most common, so an M2-specific statistic would be almost identical. Studies have found interesting, but usually not large, differences between testing for total AMA and the M2 subtype. Certainly, the association of PBC with AMA is through the M2 subtype.

I think you can safely assume that all 0.5% are associated with titers of more than 1:40 (corresponding to more than 25 units), as these are the standard accepted definitions of positive.

Why do some doctors diagnose based on AMA alone? I don't know, but it's certainly not a best practice to do so, based on the statistics you cite above. I'm speculating, but some possible reasons include: (1) Not knowing any better; (2) To reduce expense and risk associated with biopsies; (3) Influence from statistics such as the ones you cite above, and so on.

Now to your most salient question--the apparently contradictory nature of patients studied through follow-up vs. general population statistics on AMA vs. PBC. I have noticed this myself. It's a paradox indeed, and one that very little has been written about. I want to be clear again that I'm not a doctor and have no medical training, but from my research, I can think of two possible drivers of the disconnect. Both of them center around selection bias in the statistics.

1. Gender differences. As I've documented elsewhere, AMA is equally prevalent in men and women. In the largest study I'm aware of, it was actually found to be twice as common in men (0.9% vs. 0.4%). Yet the PBC gender ratio is at least 9:1 female: male. From this it follows the association of AMA with PBC is stronger in women. The gender breakdown in these studies is almost never reported. In one that I'm familiar with (from University of Pennsylvania), 29 AMA positive but asymptomatic patients were followed for up to 20 years, and at least 22 went on to develop PBC. However, 28 of the 29 patients were women. The authors don't report whether the man was one of the 22 with PBC, but you see the point: these studies tend not to control for gender. If the link between AMA and PBC relies upon hormonal differences, as some have suggested, then this is a relevant thing and it should be controlled for.

2. Comorbid autoimmune diseases. This is related to #1, because autoimmune disease generally is more common in women than men. But note the context of the study you cite above: a rheumatology clinic. In other words, arthritis. Arthritis is an autoimmune disorder! Of course if you follow a bunch of people who already have autoimmune disease, and they all also have AMA, a good number of them are going to also develop PBC--a related autoimmune disease. That's not a real test. A real test would follow members of the healthy population, and control for factors such as other autoimmune diseases and gender. These are related, of course, because arthritis is also more common in women than men: cdc.gov/arthritis/data_stat... But AMA isn't part of the standard liver panel that people get with annual physicals. So the healthy people go undetected, never get biopsied, and never count in these percentages. Meanwhile, those whose initial liver tests give cause for concern (e.g. due to symptoms, enzyme elevations, or just a history of autoimmune disease) get tested, and in those individuals we find a stronger correlation.

To bring it all together, suppose (in line with the statistics above) that there are 30,000 people (15,000 men and 15,000 women). The AMA rate is 1% among men (150 men) and 0.5% among women (75 women), for a total of 225 people. The PBC rate is in 3000 (10 people). Moreover, the PBC gender ratio is 9:1, meaning of the 10 people with PBC, there are 9 women and 1 man. All of these have co-morbid autoimmune disease.

In this example, the rate of PBC among those with AMA-positivity is 4.4% (10/225).

Now suppose you do a study, with follow-ups, biopsies, the whole nine yards. It's not possible to routinely biopsy healthy people, so you look in clinics where people are already being treated, having blood drawn, have other autoimmune diseases, etc. Suppose that you find 12 such people, 11 of whom are women. Finally, suppose that the 10 people with PBC are in this group.

In this example, you would conclude that the rate of PBC among AMA-positive people is 83% (10/12), when in fact it is 4.4% (10/225). The imbalances in gender and co-morbid autoimmune disease would not be reported.

Obviously, I made up these numbers, but I believe it illustrates how selection bias can cause the discrepancy you cite.


Hi Kevin,

I wasn't aware that AMA is more common in men than women. I guess statistically speaking then that's good news for you and bad news for us women. It sounds like more research is needed that is scientifically done to include all the variables as to clear up any discrepancies in diagnosing. Since, it's not as common as other more known autoimmune disorders it likely won't get as much funding for research. I'd like to know why autoimmune disorders are on the rise anyway especially in industrialized countries. It seems far to often that someone that I know is being diagnosed with Lupus, MS or the like. I've looked into this only a little and I've come across the "hygiene hypothesis" and the leaky gut theory, but the later is more often than not, I think, is used to fleece your pockets by alternative Drs. Been there and done that with our autistic son, who his Dr. wanted to put him on a gf/cf diet with $300 a month worth of supplements that he just so happened to sell from his store, but aside from that, a part of me wonders if there isn't some legitimacy to gluten being a problem. Even though, I've had the biopsy and it was clear of PBC, I can't help but think I still have it based on the fact I'm middle aged, have a co morbid autoimmune disease (thyroid) and fluctuating liver enzymes. My last test ALP was elevated slightly by 7 points and ALT high at 60, and a month and a half before that all three were elevated but even when ALP goes back into the normal range on retesting it's always at the upper end of the range. I also know that a liver biopsy in PBC can be subject to sampling errors. I also realize that I have a fatty liver and that could explain my elevated liver enzymes, but I would expect more isolated elevations in ALT mainly and some AST as well, but not ALP so much. I just don't know, so it still worries me! Anyway, when I go back to the liver Dr. in Jan. I will have some good questions to ask, thanks in part, to our conversation over the last few days. Thanks again for responding to my dumb questions. I definitely learned something new! Stay well!


Hi Peridot, Gritty and Kevin. Hello DianneS and Jean43.

Sorry for the break in replying. I was busy coming to India from Germany then searching out a good hepatologist here, getting an appointment and then the tests.

Kevin and Jean, you have cleared certain points so nicely in your comments.

Now to update my current status. The hepatologist got some tests repeated along with a few new ones. Depending on the result he said he will consider liver biopsy for me. Also seeing my reports from Germany he asked me to continue with Urso. Now a few of the test results too have come and i m yet to get the next appointment. AMA has now turned positive which was earlier negative. But as i wrote in my earlier post M2:3E is more advanced than AMA so probably only that was positive in the early disease (in June) and now probably the disease has advanced further that AMA has turned positive (in September). Now anti smooth muscle antibody ASMA (1:80) has also come out positive. Its a marker for autoimmune hepatitis AIH. Now that the picture has become even more complicated the hepatologist is quite likely to say yes for liver biopsy. Also i read that AIH can occur any time during PBC. In addition to Urso it requires immunosuppressive therapy and the prognosis is naturally worse than with PBC alone. This has added to my stress so much more.

I would appreciate your knowledge and experience on the above new addition.

1 like

Hello Memehta,

Yes, I do remember hearing of the M2:3E and its just a more sensitive test and if my understanding is correct it will pick up the antibody when AMA test has been negative. I hadn't heard of the PML before you mentioned it but I have heard of the sp100 and it was related to PBC. You may be in a preclinical stage of PBC and if they offer you a biopsy, I would take it. The 2 articles on ASMA, that Ive read also point to AIH, what does your Dr. think about the new bloodwork or have you seen him yet. If your like me you pick up your reports before you have even seen the Dr. Here's the articles I've came across that may be helpful to those here who havent heard of them

ncbi.nlm.nih.gov/pubmed/225... healthline.com/health/anti-... clinchem.org/content/55/5/9...


PBC/AIH overlap syndrome is rather unusual compared to PBC alone. I wouldn't jump to any conclusions. I agree that a biopsy is the logical next step. Let us know what the results are and let's go from there. In the meantime, relax, focus on things you enjoy, try not to think about it. Check in again when you have the results from the biopsy.

To recap: You are AMA and and ASMA positive, and you haven't had a biopsy. Are your liver enzymes and/or IGM elevated?


Hi Jean and Kevin.

Thanks for your helpful replies.

I agree with Jean that I may be in the preclinical stage of pbc. I too sincerely hope my diagnosis stays there. As Kevin also correctly pointed out the PBC/AIH overlap syndrome is more unusual than pbc alone. But because the ASMA also turned out positive in 1:180 titre strongly suggestive of AIH with faster progression is more fatal, so to rule it out my hepatologist strongly recommended liver biopsy. I got it done last week and am awaiting its results. As soon as the report is there I will meet my doctor and will certainly share it all with you both.

To recap:

I am M2:3E, AMA, SP100, PML, ANA and ASMA positive.

IgG, IgM and liver enzymes (AST, ALT, ALP GGTP) are not elevated and pANCA came out negative in the latest blood workup.


Hi Jean and Kevin.

I got the answers finally after a long wait. My biopsy reports Non-specific reactive hepatitis. As per my hepatologist mild changes are seen in my liver biopsy that are a mixed picture of PBC, AIH & NASH. Such changes are possible in early stages of all the 3 above. You were right Jean, he called it Subclinical PBC. Kevin unfortunately the unusual PBC/AIH overlap has come out positive in me with added unexpected NASH. NASH is progressively damaging form of Fatty Liver. He prescribed 1200mg Ursodiol per day (20mg/kg body weight). For NASH his advice is to reduce weight and take multi-vitamins especially Vit B and E. As regards to AIH he feels the side effects of immunosuppressive therapy will be more than the benefits at this early stage. So I should review after 4 months with all liver biochemistry plus above medicines.

Now my concern is that Doc has asked me to review after 4 months with liver biochemistry to check for improvement. But these are already normal. As just the liver biopsy showed mild early changes suggestive of the above diseases, repeat liver biopsy the only way any improvement can be observed in me. Has any of you heard of liver biopsy being repeated to look for the effect of ursodiol treatment. And if yes what is the earliest time that liver biopsy can be repeated after the first and how risky is that......poking the liver again soon.

Waiting eagerly for your helpful encouraging replies.


Hi Mmehta,

I'm sorry about your diagnosis. I was hoping for the best, but figured you might eventually end up with a PBC diagnosis. I'm glad they caught it early and are promptly treating it. To be honest, most of my research has focused on diagnosis, but I will look to see what I can find as far as repeat biopsies go. If I were you, I would also repost your question in a new post and see what others who have lived it, have to say about it. On those occasions, that there is a repeat biopsy I would think it would be due to a worsening condition. It probably also depends on where you live, for instance in the US they are more likely to do biopsies than if we're from the UK. Even then, I would think they would more than likely to go by your liver enzymes as to whether the Urso is working or not. Did your Dr. mention a possible repeat biopsy in the future? I'm glad I checked back on this post. I had checked the follow button, but I don't recall seeing any alerts of anything new being posted, so I'm sorry for the delay in my response! Your in my thoughts and prayers and please keep us posted on how your doing!


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