Could this be Wilsons

• By Heron
• Posted January 25, 2009 at 10:24 pm
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Have you checked out the UK WD website? http://www.wilsonsdisease.org.uk/WDSG-P0.asp
It sounds as though a 24 hour urine would be the best next step, given your test results so far. I'm not a doctor, just a WD patient, but that would be my feeling.

Your age would be within the classic range for WD. I was diagnosed at 53 myself, with symptoms somewhat similar to yours when they were first noticed. Unfortunately by the time I was actually diagnosed, my liver disease had progressed to cirrhosis. I'm doing well now, following treatment, so diagnosis pays off!

Ann

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• By whoknows
• Posted January 26, 2009 at 10:52 am
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Thanks Ann for your post, Its great to have a forum like this where one can find some support and feel understood.

I have seen the UK WDA website though I do not think they have a discussion forum like this one?

How long was it between when you first noticed the symptoms and by the time it was diagnosed as WD? How is your Cirrhosis now? How are you being managed on Zinc or a drug?

I dont understand if my free serum copper is Nil, how can the copper be deposited any where in my body except the liver. Then why my tics?

Did you have a liver biopsy done. Liver biopsy scares me. Reading through stuff I also could not fully understand the clinical use of liver biopsy given the risks. I would appreciate if someone could explain a bit. In case if Caeruloplasmin is low and urinary copper is high, Does it makes sense to get on the treatment anyway? In such a case what does liver biopsy tell us which is necessary for the clinical management that we cant know from a non invasive techniques such as Fibromax and Fibroscan etc. These techniques however, do not measure the copper content of the liver. So I guess my questin boils down to that Is there a condition in which Caeruplasmin is low, Urinary copper is high and liver copper is low or normal. What is the diagnosis then? And how is it clinically managed.?

Is there a forum for health care practitioners interested in Wilson's disease?

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• By Heron
• Posted January 27, 2009 at 1:06 am
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Hi,

I'll try to answer your questions. Please forgive the long post!
1) If your ceruloplasmin is low and your 24 hour urine copper is high, you probably have WD. Low serum copper would be consistent with that diagnosis, as I've tried to explain below. I'm not sure what you mean by low liver copper. Perhaps you mean liver copper as measured by a liver biopsy? I've never heard of a case where liver copper was low, but 24 hour urine copper was high - if it happened I'd consult with a WD expert.

2) As far as WD itself, it's best managed with a combination of a chelator (usually trientine) and zinc until urine copper levels come down to close to normal, and then with zinc alone. Some people can't tolerate zinc and continue with a chelator.

3) My own symptoms when the docs first picked them up were just elevated liver enzymes and I didn't notice them myself. During the first round of tests I also got a liver biopsy, but the doctor had already erroneously ruled out WD, so he didn't test for copper. The biopsy did not hurt particularly, but it's generally not needed unless the other test results come out ambiguous.

Between the first high enzyme test and diagnosis was about 2 years. However, before that I'd been subject to bouts of what I thought of as a "sensitive stomach" for years and I think that other things, such as intense emotional ups and downs and a lot of anxiety were also related, although there's no way to prove it.

Over the two years between the first test and the final diagnosis, I noticed other things little by little, such as fatigue, stumbling, and cramps in my hands and feet. Then as my liver started to fall apart, I felt and then looked more and more bloated (from ascites ie fluid buildup), my ankles swelled, and I had a hard time eating.

Now, after 6 months of trientine plus zinc and then 6 years of zinc alone, I feel mostly quite normal and my labs also are mostly normal. Even my platelets, which were low for years, were within normal range in December. I still have cirrhosis, but my liver works pretty well in spite of it.

It's normal for serum copper to be low in WD patients even though urinary copper is high. I think it's because ceruloplasmin bound copper gets excreted through the feces, not the urine, and in a person who doesn't have WD, that means that very little copper gets excreted through the urine.

Do you know how your doctors computed your "free" copper? Based on the numbers you give for serum copper and ceruloplasmin, it is probably not really 0, but I'd have to know the units in which they were stated to say for sure. For what it's worth, here's how you do it:

It all turns on the fact that copper makes up only about 0.3% (.003) of a ceruloplasmin molecule. Thus to calculate "free" copper, that is the copper in the blood that is not bound to a ceruloplasmin molecule,
1) Do whatever it takes to convert serum copper and ceruloplasmin into the same units. The most convenient units to use are micrograms (ul) per decaliter (dL).
2) Then multiply .003 times your ceruloplasmin. This gives you the amount of copper that is bound to ceruloplasmin.
3) Subtract the result from the total serum copper and you have the amount of copper that is not bound to ceruloplasmin.

There are 1,000 micrograms in 1 milligram. Thus if you want to state ceruloplasmin in milligrams (mg) instead of micrograms (ug), you divide the number of micrograms by 1,000. If you state the numbers this way, you multiply the amount of ceruloplasmin by 3 instead of .003. This is the shortcut on the WDA site used by many doctors, probably because ceruloplasmin often is stated in milligrams.

Using my last year's labs as an example, My ceruloplasmin was 7.5 milligrams (mg's) per decaliter. Multiplying by 1,000 gives 7500 micrograms per decaliter. .003 of this was copper. 7500 times ,003 = 22.5 micrograms (ug's) per decaliter.

My copper serum was 0.36 micrograms per millileter (mL). There are 100 millileters in one decaliter, so I multiplied by 100 to get the number of micrograms per decaliter, giving me 36 micrograms of copper per decliter. 22.5 micrograms were bound to the ceruloplasmin. Subtracting that from the total tells me that 13.5 micrograms of copper per decaliter were not bound to ceruloplasmin.

I hope this makes things clearer rather than more confusing. The shortcut formula would work better if labs consistently stated serum copper in ug/dL, but they don't. Then people try to follow the shortcut formula, end up with negative numbers or zero, and get confused.

4) I don't know of a forum for health care practitioners interested in WD, but they can contact the centers of excellence listed on the WDA website for information.

Ann

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• By whoknows
• Posted January 27, 2009 at 8:15 am
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Dear Ann,

Thanks for your message, my comments are as follows:

1) I am still confused on this as in situations where liver function values are abnormal, Caeruplasmin is low, urinary copper is high, KF rings are absent WDA recommends liver biopsy for diagnosis see the chart in the following document:

http://www.wilsonsdisease.org/pdfs/WDbrochureAlgorithm.pdf

Also see figure 2 in the following document which depicts the possibility that inspite of all of the above liver biopsy may reveal low copper content. I am wondering what conditions could result in that:

http://www.aasld.org/practiceguidelines/Documents/WilsonDisease2008.pdf

2) Yes I have read that. Though it seems to me that a combination of natural copper chelators such as polyphenols (Free Radical Research 36:1109-208,2002) with Zinc and other natural compunds may result in lower doses of all these compounds being used and therefore perhaps less side effects. However, I can see that no trial of these chelators specifically for WD has been carried out. As these natural compounds are not patentable and therefore it would not make financial sense for a drug company to sponsor a trial, WDA and patients need to lobby with universities and practitioners for such trials.

3) Have all your neurological symptoms such as anxiety also totally reversed?

My lab has measured my plasma copper as low at 9 umol/litre which is micromole per litre. Whereas they have measured my Caeruplasmin as 0.19 g/Litre. I do not know the conversion of copper's micromoles into grams. Any help here would be appreciated.

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• By Heron
• Posted January 27, 2009 at 9:07 pm
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Hi,
1) I haven't looked at everything on the WDA site in awhile, so I hadn't seen that brochure until now. It seems ultra cautious in basically recommending liver biopsy in anyone without KF rings, but I'm not a doctor. Looking at the Schilsky-Roberts article, it appears to say the same thing in the chart, but in the text it suggests that if the result of a 24 hour urine copper test is high enough (over 100), the diagnosis is established. Either way, a 24 hour urine is standard procedure and I still think for you should probably be the next logical step. It's not a lot of fun, mostly because it's embarrassing, but believe me, it's a million times better than acute WD symptoms! Remember, you're not alone in doing it; all of us have to go through it.

2) I have learned a lot about the medical system by having WD, including the obstacles to getting "natural" compounds tested so that we can compare them to the ones that can be patented. I believe in natural remedies most of the time, but not so much for WD. I know some great herbal healers, but they are very unlikely to meet enough WD patients (or any) to get the experience to deal with the condition, and for the same reason, I don't think that folk traditions could evolve to deal with it. I feel lucky that zinc, a relatively "natural" solution, works well for me and most WD patients. There was one woman on the WD list-serve who discovered through her own experiments that zinc lessened her tremors, well before she was diagnosed.

3) It's really hard to measure anxiety. I think it decreased, but that might be partly because I finally understood what was going on. My foot, leg, and hand cramps decreased a whole lot. So did the stumbling and other subtle symptoms that could be considered neurological. In some way my life just seemed to get better and make more sense. But I still feel like I move a little slower than most people and have a lower threshold for anxiety, depression, and anger. Luckily, I know how to work with all of them, partly by identifying them as WD.

4) 9 umol/litre is so low that I'm not sure how you would apply the test to it. I do know that there are different ways of measuring ceruloplasmin and some labs include "apoceruloplasmin" in the results. "Apoceruloplasmin" has not yet bonded to copper. If you include this in the measurement, it throws off the result in terms of an eval for WD. Perhaps that could explain your results. Shilsky-Roberts refer to this problem in their discussion of serum copper and free copper, but word it in terms of the ceruloplasmin that has bonded to copper, known as Holoceruloplasmin.

So I still say get that urine test. If your doctor recommends a liver biopsy as well, get that too.

Best of luck,
Ann

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• By whoknows
• Posted January 28, 2009 at 1:52 am
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Thanks for all your very helpful comments. Meeting the doctor today. Will aim to get a repeat blood work, 24 hour urine copper, liver ultrasound and eye specialist referral for identification of KF rings. Lets see how much I get from the doctor. Will update you on how it goes.

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• By whoknows
• Posted January 28, 2009 at 2:45 pm
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Hi Ann,

So had to deal with a doctor who had no idea of what wilson's could be. He said in his last 30 years of practice he has just seen one person with Wilson's and I cant have it. He was also surprised that why did the previous doctor (its a clinic with rotating doctors) agee to test copper levels. He felt that as copper levels are high in Wilson's and mine are low therefore I cant have Wilson's. After a bit of explanations and persistance from me, he thought it would work best to just write what I am requesting so now I have a 24 hour urinary copper, repeat blood tests and a liver ultrasoun prescribed. He felt tht the referral to the ophtamalogist should only come if urinary copper is high. I can live with that.

By the way I have also worked out how my free copper was caclulcated. So it turns out 8umol=500mcg of copper. I found this in Roberts and Schilsky paper. Using that ratio I converted first the Caeruloplasmin at 0.19g/litre to mcg which turns out to be 19,000MCG/Litre multiply it by 0.03 (I used 0.03 instead of 0.003 as I am using Litre instead Deci Litre) and you have 570 as bound copper. Now plasma copper was 9umol/Litre which converted into mcg per litre gives me 562.5 which is very close and therefore we have 0 on my free copper reading.

Now could I have Wilson's with this? This seems to be more of a copper deficiency?? Anyways urinary copper will tell.

Also a common cold started yesterday(last episode was an year ago) and I am wondering if going for Caeruloplasmin repeat now is a good idea as its levels can be raised with inflammation or acute disease? Ofcourse my doctor didnt care about this.

One more question, in the Roberts and Schilsky paper discussing the goal for excretion of copper on trientine they write:

"Values of urine copper excretion below 200
mcg/day (3.2
umol/day) may indicate either nonadherence to therapy or overtreatment and excess copper removal."

Whereas discussing Zinc therapy they write:

"Adequacy of treatment with zinc is judged by clinical
and biochemical improvement and by measuring 24-hour urinary excretion of copper, which should be less than 75 mcg (1.2
umol) per 24 hours on stable treatment."

Why this different approach to monitoring? Copper is copper? Unless its because Zinc also uses fecal route to eliminate copper whereas other drugs mainly do it through urine. Could this be the reason?

Many thanks for all your help in navigating this part of life:)

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• By Heron
• Posted January 28, 2009 at 10:33 pm
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Hi,

I'm glad that you've persuaded your doctor to do the tests. Now you will know one way or the other. Congrats on figuring out the ceruloplasmin calculations - it took me a long time.

You're exactly right about the reason for the different approaches to monitoring with zinc and chelators. Zinc blocks copper from getting into your system. It gets bound to metallothionein in the gut and then excreted in the feces, never getting to the liver or into the circulatory system. On the other hand, chelators keep the copper moving through your system (relatively) safely and then it's excreted through the urine, so urine levels stay higher.

It sounds like you are navigating quite well!

Ann

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• By Heron
• Posted January 31, 2009 at 4:52 pm
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Hi,
Just an addition to respond to your other questions:
1) By the way I have also worked out how my free copper was caclulcated. So it turns out 8umol=500mcg of copper. I found this in Roberts and Schilsky paper. Using that ratio I converted first the Caeruloplasmin at 0.19g/litre to mcg which turns out to be 19,000MCG/Litre multiply it by 0.03 (I used 0.03 instead of 0.003 as I am using Litre instead Deci Litre) and you have 570 as bound copper. Now plasma copper was 9umol/Litre which converted into mcg per litre gives me 562.5 which is very close and therefore we have 0 on my free copper reading.

Now could I have Wilson's with this? This seems to be more of a copper deficiency?? -

Almost all WD patients have low serum copper, though your is even lower than most of us. If your liver is still storing most of the free copper and it hasn't built up enough to spill over into the blood, it seems as though serum copper could approach zero? The whole question of how and why copper balances are high and low in a WD patient gets very complex. It appears to move or not move through us in strange unexpected ways. So I'd say your results could be compatible with WD, but I'm not a doctor.

2) Also a common cold started yesterday(last episode was an year ago) and I am wondering if going for Caeruloplasmin repeat now is a good idea as its levels can be raised with inflammation or acute disease?

I don't think a cold would affect ceruloplasmin. Acute liver disease could affect it, but it doesn't sound as though you are anywhere near that point.

Ann

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• By whoknows
• Posted February 1, 2009 at 11:55 am
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Thanks Ann,

1) Agree with you that this could be Wilson's we shall know with the result of urinary copper testing.

2) You are right a cold may not affect it a lot, however, in theory any acute desease can increase inflammation, I just want to be very sure. Cold is now clearing, also this coming week my work will be very busy so I will go next week. In the mean time, I have stoppedy multi vitamin which has copper and other very high copper foods such as nuts, live etc.

3) Have you ever seen the following studies:

http://tpx.sagepub.com/cgi/content/abstract/33/5/584

and

http://www.ncbi.nlm.nih.gov/pubmed/18622472?ordinalpos=6&itool=EntrezSystem 2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDoc Sum

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• By Heron
• Posted February 1, 2009 at 2:38 pm
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No, I hadn't seen those studies or heard of N-acetylcysteine. They are very interesting.

Good idea to stop the supplement containing copper and the nuts for now, as long as you're still getting a balanced diet. Once copper levels have stabilized and especially if you go with zinc, you can pretty much have all the nuts you want, but the supplements are still out. Why people want to add copper to them escapes me, since most people get plenty of copper.

Be well,

Ann

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• By whoknows
• Posted February 2, 2009 at 3:53 am
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Here is one more study which may be of inerest to you, LEC rats are a model for Wilson's type disease in rats:

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T74-458W8XH-5&_u ser=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version= 1&_urlVersion=0&_userid=10&md5=a5b46e09e8f16a24f02ff43f38ef37c3

Inhibition of liver fibrosis in LEC rats by a carotenoid, lycopene, or a herbal medicine, Sho-saiko-to


Yukihiro Kitade, , a, Seishiro Watanabea, Tsutomu Masakia, Mikio Nishiokaa and Hoyoku Nishinob

a Third Department of Internal Medicine, School of Medicine, Kagawa Medical University, 1750-1 Ikenobe Miki-cho, Kita-gun, Kagawa, 761-0793 Japan

b Department of Biochemistry, Kyoto Prefectual University of Medicine, Kyoto, Japan


Received 30 December 2000; revised 16 May 2001; accepted 25 June 2001. Available online 5 March 2002.

Abstract
We assessed the prevention of hepatic fibrogenesis by a herbal medicine Sho-saiko-to or a carotenoid lycopene in Long-Evans rats with cinnamon coat color (LEC rats). LEC rats were divided into three groups: A (n=40), fed on a basal diet (BD); B (n=25), fed on BD plus 1% Sho-saiko-to; and C (n=40), fed on BD plus 0.005% lycopene. All rats were sacrificed at 76 weeks of age. The liver tissues were stained with Azan–Mallory and α-smooth muscle actin (α-SMA). The malondialdehyde (MDA) in the liver was measured for the assay of lipoperoxides. The percentage of the total area stained was determined morphometrically. The percentage of the total area involved by fibrosis was 1.35±0.56 in group A, 0.72±0.34 in B (P=0.0020, B vs. A) and 0.78±0.75 in C (P=0.0031, C vs. A). The percentage of the total area that was stained for α-SMA was 0.61±0.57 in group A, 0.11±0.05 in B (P=0.0017, B vs. A) and 0.12±0.06 in C (P=0.0021, C vs. A). In group B, MDA in the liver was lower than in group C (P=0.009). In group C, the concentration of iron in the liver was lower than in group A (P=0.0059). In conclusion, Sho-saiko-to suppressed fibrogenesis through reduced generation of lipid peroxides. Hepatic fibrogenesis was also suppressed by lycopene. The mechanisms of this preventive effect of fibrogenesis with Sho-saiko-to and lycopene were suggested to inhibit the stellate cell activity.

Author Keywords: LEC rats; Lycopene; Sho-saiko-to; Fibrosis


Lycopene is found in Tomatoes specially cooked tomatoes or tomato sauce and has other health benefits too.

For the sake of everyone the abstracts from links in my last post are as follows:

Effects of N-Acetylcysteine, Quercetin, and Phytic Acid on Spontaneous Hepatic and Renal Lesions in LEC Rats
Yasuki Kitamura1, Akiyoshi Nishikawa1, Hideaki Nakamura1, Fumio Furukawa1, Takayoshi Imazawa1, Takashi Umemura1, Koji Uchida2 and Masao Hirose1
1 Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
2 Nagoya University Graduate School of Bioagricultural Sciences, Nagoya 464-8601, Japan

Correspondence: Address correspondence to: Akiyoshi Nishikawa, Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan; e-mail:nishikaw@nihs.go.jp

The effects of anti-oxidants were examined in Long-Evans Cinnamon (LEC) rats, which develop acute hepatic injury, and subsequent hepatic and renal tumors due to accumulation of excess Cu. The rats, at the age of 15 weeks, were supplied a diet containing either 1% of N-acetylcysteine (NAC), quercetin (QC), or phytic acid (PA), or basal diet alone. At weeks 2 and 6 posttreatment, animals were sacrificed for collection of blood and tissue samples. In the NAC-treated group, the development of hepatic and renal lesions was dramatically reduced. In addition, accumulation of Cu and Fe in the liver was suppressed. Acrolein-modified protein, a new marker for lipid peroxidation, was not detected in the liver or kidney of NAC treated rats, even though deposition was evident in control. Neither QC nor PA affected the development of spontaneous hepatic lesions. These results indicate that oxidative stress was reduced by NAC in the liver and kidney, and suggest that Cu and Fe may be involved in the generation of oxidative stress in the liver. In addition, it was suggested that the different effects of the anti-oxidants on lesion development in LEC rats might be related to different mechanisms of action with regard to oxidative stress.


Key Words: Anti-oxidants • N-acetylcysteine • quercetin • phytic acid • LEC rat • acrolein-modified protein • oxidative stress: glutathione

and

Role of N-acetylcysteine on fibrosis and oxidative stress in cirrhotic rats.Pereira-Filho G, Ferreira C, Schwengber A, Marroni C, Zettler C, Marroni N.
Federal School of Medical Sciences of Porto Alegre, RS.

BACKGROUND: Hepatic cirrhosis is the final stage of liver dysfunction, characterized by diffuse fibrosis which is the main response to the liver injury. The inhalatory carbon tetrachloride is an effective experimental model that triggers cirrhosis and allows to obtain histological and physiological modifications similar to the one seen in humans. AIM: To investigate the effects of N-acetylcysteine (NAC) on the fibrosis and oxidative stress in the liver of cirrhotic rats, analyzing liver function tests, lipoperoxidation, activity of glutathione peroxidase enzyme, collagen quantification, histopathology, as well as the nitric oxide role. METHODS: The animals were randomly in three experimental groups: control (CO); cirrhotic (CCl4) and CCl4 + NAC. Evaluate the lipid peroxidation, the glutathione peroxidase enzyme, the collagen and the expression of inducible nitric oxide synthase (iNOS). RESULTS: The cirrhotic group treated with N-acetylcysteine showed trough the histological analysis and collagen quantification lower degrees of fibrosis. This group has also shown less damage to the cellular membranes, less decrease on the glutathione peroxidase levels and less expression of inducible nitric oxide synthase when matched with the cirrhotic group without treatment. CONCLUSION: N-acetylcysteine seams to offer protection against hepatic fibrosis and oxidative stress in cirrhotic rat livers.

PMID: 18622472


You are right that most people have adequate copper intake, I think added copper in multivitamins is there to balance the additional Zinc being provided by those multivitamins. Else there is a risk that the added Zinc could cause a copper deficiency in people who otherwise had adequate copper intake via food.

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