Could Some Patients With Fibromyalgia Potentially Have Hypophosphatasia? A Retrospective Single-Center Study 2023 Injean et al

[Andy]

Abstract

Objective
Hypophosphatasia (HPP) is a rare disease characterized by incomplete or defective bone mineralization due to a mutation in the alkaline phosphatase (ALP) gene causing low levels of ALP. Disease presentation is heterogeneous and can present as a chronic pain syndrome like fibromyalgia (FM). Our objective was to determine if there are any potential patients with HPP in the group of patients who were diagnosed with FM. Antiresorptive therapy use can trigger atypical femur fractures in patients with HPP.

Methods
We performed a retrospective chart review of all patients 18 years or older at a single academic center who were diagnosed with FM and had either a low or a normal ALP level. The following characteristics were reviewed: biological sex; age; history of fractures; diagnosis of osteoporosis, osteopenia, osteoarthritis, and chondrocalcinosis; genetic testing; vitamin B6 level testing; and medications.

Results
Six hundred eleven patients with FM were identified. Two hundred had at least one low ALP level, and 57 had at least three consecutively low measurements of ALP, 44% of which had a history of fractures. No patients had vitamin B6 levels checked. None of the patients had previous genetic testing for HPP or underwent testing for zinc or magnesium levels.

Conclusion
The percentage of patients with FM who were found to have consistently low ALP levels was 9.3%. None had vitamin B6 level or genetic testing, suggesting that the diagnosis was not suspected. It is important to diagnose HPP given the availability of enzyme replacement therapy to prevent complications from HPP such as fractures. Our data support screening for this condition as a part of the initial workup of FM.

Open access, https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/acr2.11591

 

[Ash]

That great for the people who were identified as having this condition isn’t it, they otherwise would of languished until complications really escalated and probably even after that.

 

[Hutan]

No particular person was identified as having HPP; the authors were working with de-identified data. They are just saying, we looked at some medical records, and a substantial number of people warrant further investigation for HPP.

According to the Tissue Nonspecific Alkaline Phosphatase Gene Mutation Database, the prevalence of the severe form of the disease is 1 in 100,000; however, the less severe forms are reported to be as common as 1 in 6000 (2, 3). HPP has a spectrum of severity and is characterized as a defect in bone mineralization leading to fractures and, perhaps most similarly, muscle pain, chronic pain, and osteoarthropathy (2, 4-7). There are case reports that have described patients with adult-onset HPP who were initially misdiagnosed with FM (4, 7, 8).

Although FM and HPP may present similarly in their clinical signs and symptoms of chronic musculoskeletal pain, an accurate diagnosis would guide treatment discussion and counseling. Thus, it is essential to be able to identify patients with HPP who may be mistakenly diagnosed with FM. Alkaline phosphatase (ALP) should be normal in patients with FM and low in patients with HPP due to any number of mutations in the ALP gene. A history of premature tooth loss may be present in those with HPP and is not a feature of FM, so a dental history should be obtained in patients with chronic musculoskeletal complaints. If HPP is suspected in a patient with a low ALP level, vitamin B6 levels and phosphoethanolamine (PEA) levels in either urine or serum (which are elevated in HPP) should be checked after alternative reasons for a low ALP level have been ruled out. Genetic testing is desirable but not required for diagnosis (3, 9, 10).

Due to the heterogeneity of presentation of clinical signs and symptoms, lack of awareness, and overlap of presentation with common conditions, HPP is often underdiagnosed or misdiagnosed (11-13). The identification of patients with HPP is important because HPP may result in an increased incidence of atypical femur fractures.

This sounds important. Here's a genetic disease that can be clearly diagnosed and treated, but people are not being given the appropriate screening. From the symptoms listed, there are probably people diagnosed with ME/CFS who have this condition too.

It looks like this is something that deserves more studies.

@Andy, @Chris Ponting, @Simon M - 'a mutation in the alkaline phosphatase (ALP) gene causing low levels of ALP'. There could be an interrogation of the DecodeME data to see if there are possibly misdiagnosed people in the sample.

 

[Ash]

Thanks @Hutan. I only read conclusion of above post. I hope these study results get out and patients start demanding genetic testing. I know there isn’t capacity but only way to increase it is like loud demand.

 

[Hutan]

I hope this study results get out and patients start demanding genetic testing. I know the isn’t capacity but only way to increase it is like loud demand.

Yes. From the paper, it looks as though there are ways to stage the testing, and genetic testing isn't strictly necessary. But it does sound as though screening for this condition in people who present with fibromyalgia (and probably ME/CFS with muscle pain) would be useful.

 

[Sean]

I have the opposite, consistently high ALP every time it has been measured since I got ME.

The most consistent (abnormal) lab finding in my medical history.

 

[Ash]

I have the opposite, consistently high ALP every time it has been measured since I got ME.

The most consistent (abnormal) lab finding in my medical history.

I don’t know what ALP is really having only just been prompted to think about it. Why do Drs order tests for it generally?

 

[Hutan]

https://medlineplus.gov/lab-tests/alkaline-phosphatase/

What do the results mean?

High alkaline phosphatase (ALP) levels may be a sign of a liver problem or a bone disorder. Liver problems and bone disorders cause different types of ALP. But your test results can't tell which type of ALP is high.

If your test results show high ALP levels, your provider may order other tests to help figure out what's causing the problem. These tests may include:

• An ALP isoenzyme test. This test can tell which part of your body is making the ALP. But this test may not available everywhere.
• Liver function tests. If the results of these tests are also high, then your high ALP level is likely from a problem in your liver.

High alkaline phosphatase levels from your liver may be a sign of:

• Blockages in the bile ducts
• Cirrhosis
• Hepatitis
• Mononucleosis, which can sometimes cause swelling in the liver

If alkaline phosphatase levels are high and the results of liver tests are normal, the problem may be a bone disorder, such as Paget's disease of bone. This disease makes your bones unusually large and weak, causing them to break more easily.

Moderately high levels of ALP may be a sign of a many different types of conditions, including Hodgkin lymphoma, heart failure, or certain infections.

It's possible to have higher than normal levels of ALP and not have a medical condition that needs treatment. Your provider will consider your symptoms, medical history, and other test results to make a diagnosis.

Low levels of ALP are less common. They may be a sign of a lack of zinc, malnutrition, pernicious anemia, thyroid disease, Wilson disease or hypophosphatasia, a rare genetic disease that affects bones and teeth.

Learn more about laboratory tests, reference ranges, and understanding results.

Is there anything else I need to know about alkaline phosphatase test?
Many things can affect ALP levels. Pregnancy can cause higher than normal ALP levels. Children and teens may have high levels of ALP because their bones are growing. Birth control pills and certain medicines may lower ALP levels, while other medicines can cause the levels to increase. Even eating a fatty meal before an alkaline phosphatase test may also cause a small increase in ALP.

 

[Kitty]

I was diagnosed with this, but as far as I know it's the form that only affects teeth. It was suspected when I started losing some of my permanent teeth in my teens.

I'm going back decades, so there were no genetic tests, only X-rays. I've only become aware comparatively recently that there are other types; for most of my life I just thought it was a weird dental condition that my dad and I had.

 

[Chris Ponting]

No particular person was identified as having HPP; the authors were working with de-identified data. They are just saying, we looked at some medical records, and a substantial number of people warrant further investigation for HPP.







This sounds important. Here's a genetic disease that can be clearly diagnosed and treated, but people are not being given the appropriate screening. From the symptoms listed, there are probably people diagnosed with ME/CFS who have this condition too.

It looks like this is something that deserves more studies.

@Andy, @Chris Ponting, @Simon M - 'a mutation in the alkaline phosphatase (ALP) gene causing low levels of ALP'. There could be an interrogation of the DecodeME data to see if there are possibly misdiagnosed people in the sample.

Thanks. We've looked in UK Biobank data and don't see low alkaline phosphatase levels on average. If anything it might be slightly higher.

 

[Hutan]

We've looked in UK Biobank data and don't see low alkaline phosphatase levels on average.

If only 1 in 6000 people have the HPP condition, then there probably won't be many people diagnosed with ME/CFS who actually have HPP. So, of course, they may not have much impact on the average ALP levels in people in the UK Biobank with an ME/CFS diagnosis. But, finding those people could make a big difference to them.

It is interesting that 200 of the 611 people with a diagnosis of fibromyalgia in this sample had at least one low level of ALP. It would be good to know the distribution of individual ALP values in people diagnosed with ME/CFS (and fibromyalgia) in the UK biobank - are there some people with low levels and some with high levels?

If anything it might be slightly higher.

High levels of ALP seem to be associated with liver disease and some infections. I guess it's possible that someone might have fatigue as a result of liver disease (e.g. a hepatitis) and be diagnosed with ME/CFS - and so might inflate the average. That note from Medline that I quoted above was interesting - suggesting that high ALP can be a sign of mononucleosis (caused by EBV) - could some people with ME/CFS be having intermittent reactivations that affect the liver?


(My ALP levels have been resolutely normal. I doubt ALP has much to do with ME/CFS.)