labs not consistent with HH

Very well explained, GillianA.  The Rennes group of researchers are my current favourites for up to date information on HH.

 

He doesn’t think there is a correlation.  The white blood cell stuff presented first and the myelodysplasia FISH of bone marrow was normal.  But thank you for your response.  Your information is very helpful

Where is the Rennes group?

I looked Rennes up - it's a city in the east of Brittany in northwestern France at the confluence of the Ille and the Vilaine rivers.

Here are the author affiliations from the paper I mentioned above, all based in Rennes:

*CHU Rennes, Service des Maladies du Foie and Centre National de Référence des Surcharges en Fer Rares, Rennes, France;

‡INSERM, CIC 1414, Rennes, France;

§University of Rennes 1, Faculty of Medicine, Rennes, France;

kCHU Rennes, Service de Rhumatologie, Rennes, France; and

¶INSERM UMR 991, Rennes, France

Based on Gillian’s response we both could be having unnecessary phlebotomies.  My hematologist even said he may be treating me with phlebotomy which may not even be helpful. That is why he is looking elsewhere to send me to but in the mean time is still ordering phlebotomy as long as my iron saturation is above 30

I did not mean that emoji - it was supposed to be a closing bracket  

The following are my levels. The readings begin in 2017 and prior to first reading had started supplementing with iron due to bone marrow biopsy showing no iron May/November/Jan22/           Feb2/Feb15/March 7/March27.   I had been taking iron for awhile until the November reading, stopped iron but still on multivitamin which contained iron stopped that after labs on 1/22 and discovered I was homozygous for c282y. Feb 26 liver biopsy showed stage 3 iron deposition but HII was only 1.2.  Dr thought it was only a matter of getting the iron out that I had been supplementing with.  1st phlebotomy was on 3/7 with a goal of getting saturation less than 30. Came back on 3/27 to find my saturation increased and had my second phlebotomy and that’s when my dr said this wasn’t making sense to him and he is looking other resources. Scheduled for another treatment on 4/10. 

Iron               

72/165/234/162/170/140/196

Ferritin                

67/178/203/110/69/73/67

TIBC            291/247/234/249/245/269/226

Saturation %      

24/67/100/65/69/52/87

I hope this makes sense as far as how I typed the information I appreciate the help and will look into the article to show my dr before I see him again

With a bit of reading, your dr will discover that TS% cannot be managed.  The research that Gillian referred to said the same thing in the words of something like this - just because some people's TS% reduces with vx, it does not mean it was managed to do this.  Just different metabolisms.

It has only been one year or less? since you started vx.  It will not happen overnight.  My TS% has taken 20 years to reduce, and maybe next bloods it will be up again.  Maybe yours could reduce in another year, or maybe not.  AT this stage, it is not important.  Ferritin levels are, and that is what needs to be concentrated on.  Get your ferritin to <50 and have enough vx at an appropriate frequency to maintain that level.  Ferritin, too, will go up and down, with infections (even a cold), and inflammations, etc.  Once the infection is over, it will come back down again.  Makes notes of how you feel to work out what level of ferritin is most satisfactory for you - i.e. no or reduced usual HH symptoms.

Just keep reading research and be on the lookout for some answers for this.  The Rennes groups are the first to work on it and publish.

Eventually with more knowledge,  it will become less important to you.

Best wishes

Sheryl

Actually I’ve only had two phlebotomy treatments.  I’m still newly diagnosed but after seeing my liver biopsy my dr wants hem ever 3 weeks until iron saturation was below 30.  After my 1 st treatment he said were goinf to do them every 2 weeks but also stated we may be doing these for nothing which is why wants a second opinion.  I know my last phlebotomy was11 days ago and today I’m Sooo tired.  So if nothigvwlsevatvleast I feel better after having them.  But my understanding from what everyone has said OB this post is once ferritin in below 50 I should keep up the phlebotomies and eventually iron saturation will to drop.  

Every three weeks seems too excessive if you are already in 'normal' range.  This range is not low enough if you are homozygous C282C.  Perhaps every one or two months is enough, till you get to 50, then every three months.

Don't worry about the TS% till you have been doing this for up to 6 years.

 

I guess what I’m most confused about is why dis my liver biopsy showbstage 3 hemosiderosis when my labs at that time where also pretty normal?

Hi Jessica, I’ve been wondering about that too.  I’ve been doing some digging looking for anything that might shed light on possible reasons for someone with C282Y homozygosity having high iron on liver biopsy at a time when ferritin was normal.  I’ll post more of the theory I dug out later – but for now, here is what happens when I try to put what I’ve found so far together with your test results . . . .  maybe some of this might be helpful for you in talking with your doctor?

I started by charting the lab results you’ve posted along with a rough estimate of normal values (how close did I get?)  It looks much better in Excel but basically this is the result.  (If you’d like the Excel file, you can send me a private message with your email address and I’ll email you back with the actual Excel file.)

Column headings:  Date, Ferritin, % Sat, TIBC, Iron

Normal ranges:  ferritin <200 ug/L, % Sat 15-55%, TIBC 240-450 mcg/dL, iron 50-170 ug/dL

Date                   Ferritin %Sat  TIBC      Iron

01-May-17          67           24      291          72          

01-Nov-17          178          67      247        165        Stopped iron supplement

22-Jan-18           203       100      234         234        Stopped multivite with iron

02-Feb-18          110          65      249        163        

15-Feb-18            69          69      245        170        

26-Feb-18       Liver biopsy        Iron deposition stage 3 / hepatic iron index 1.2

07-Mar-18            73           52     269         140         Phlebotomy #1

27-Mar-18            78           87     226         196         Phlebotomy #2

10-Apr-18                                                                   Phlebotomy #3 scheduled

Additional information

·   C282Y homozygosity

·   Long-standing chronic leukopenia

·   Bone marrow biopsy in 2016 showed no iron

Observations on the lab results above

·   The % saturation goes up higher above normal than the ferritin does

·   Both the % saturation and ferritin come down after stopping iron supplementation

·   After phlebotomy #1, the ferritin basically doesn’t change, but the % saturation and iron go up

·   The fact that the ferritin stayed stable after the first phlebotomy suggests that there isn’t much if any tissue iron overload

·   The increase in % saturation and iron after the first phlebotomy is consistent with HFE hemochromatosis-caused iron over-absorption being increased further by blood loss

Leading to the key question:  if the lab results don’t really support the presence of significant iron overload, what could be other possible cause(s) of the stage 3 iron deposition found on liver biopsy?

Possibly relevant theory from the medical literature:

From Calculation and interpretation of the hepatic iron index:  A brief summary.  Ann Intern Med 1999 

·   Liver iron can be high in the absence of iron overload when there is viral hepatitis, fatty liver, or cirrhosis caused by alcohol excess, etc.

·   The hepatic iron index is designed to sort out high liver iron caused by hemochromatosis vs high liver iron caused by something else

·   A hepatic iron index greater than 1.9 in a non-cirrhotic liver strongly suggests the cause is hemochromatosis / iron overload

·   However, even with no iron overload being present, liver cirrhosis on its own can cause a high hepatic iron index

·   Iron is not evenly deposited in the liver so the hepatic iron index from different spots in the same liver can vary widely (e.g., hepatic iron index results from 1.1 vs 3.0 in biopsies all from the same liver)

And from Masuzaki R et al.  Comparison of liver biopsy and transient elastography based on clinical relevance.  Can J Gastroenterol. 2008 Sep; 22(9): 753-757.

·   Liver biopsy can miss cirrhosis because only about 1/50,000 of the liver is analyzed

·   When liver biopsy doesn’t show cirrhosis, cirrhosis may actually be present up to 30% of the time

·   Cirrhosis missed on liver biopsy may be picked up by elastography to measure liver stiffness

I couldn’t find much on leukopenia in viral or autoimmune hepatitis, and much of what I found is from older literature – here’s an example.  I expect a doctor with expertise in hepatitis will know lots more –

Kivel RM.  Hematologic aspects of acute viral hepatitis.  Am J Digestive Diseases 1961

·   Acute hepatitis is associated with leukopenia, atypical lymphocytes, and macrocytosis (aka big red cells)

Putting this together suggests some questions that you might want to ask your doctor?

·   What were hemoglobin values and red cell indices?  (A post-phlebotomy drop in hemoglobin would support no tissue iron overload.)

·   Did the liver biopsy show any fibrosis (cirrhosis) or fatty liver or indications of other liver disease?

·   If liver biopsy didn’t show any cirrhosis, would it be a good idea to do liver elastography? 

·   What was the pattern of iron deposition on liver biopsy?

·   Would it be a good idea to have an MRI for iron?  (An MRI for iron can show the pattern and amount of iron deposited – or not - in the liver and elsewhere, e.g., in the spleen and bone marrow.)

·   Would it be a good idea to test for any other kinds of liver disease, such as viral hepatitis or autoimmune hepatitis (if it hasn't already been done)?

I also pasted in below a few more references below that might be of interest.  I also have links to all the references mentioned, all to full text except for the 1961 article.  I can post the links if that would be helpful, but I've found it can take days for posts with links to be approved and I know your next phlebotomy is coming up soon. If you want, you can send me your email by private message and I’ll email you the links right away.

Fingers crossed that some of this might be useful in some way -

Causes of liver iron deposition

Med Sci Monit. 2016; 22: 2144–2151.  The Role of Iron and Iron Overload in Chronic Liver Disease.  Milic S et al.  (UHC Rijeka)

Abstract

The liver plays a major role in iron homeostasis; thus, in patients with chronic liver disease, iron regulation may be disturbed. Higher iron levels are present not only in patients with hereditary hemochromatosis, but also in those with alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis C viral infection. Chronic liver disease decreases the synthetic functions of the liver, including the production of hepcidin, a key protein in iron metabolism. Lower levels of hepcidin result in iron overload, which leads to iron deposits in the liver and higher levels of non-transferrin-bound iron in the bloodstream. Iron combined with reactive oxygen species leads to an increase in hydroxyl radicals, which are responsible for phospholipid peroxidation, oxidation of amino acid side chains, DNA strain breaks, and protein fragmentation. Iron-induced cellular damage may be prevented by regulating the production of hepcidin or by administering hepcidin agonists. Both of these methods have yielded successful results in mouse models.

Interpreting liver biopsy results

World J Gastroenterol. 2007 Sep 21; 13(35): 4755–4760.   Pathology of hepatic iron overload.  Deugnier Y, Turlin B. (Pontchaillou University Hospital, Rennes 35033, France)

Correspondence to: Yves Deugnier, Professor of Hepatology, Liver Unit and CIC INSERM 0203, Pontchaillou University Hospital, Rennes 35033, France. rf.1senner-vinu@reingued.sevy  Telephone: +33-2-99284297 Fax: +33-2-99284112

Abstract

Although progress in imaging and genetics allow for a noninvasive diagnosis of most cases of genetic iron overload, liver pathology remains often useful (1) to assess prognosis by grading fibrosis and seeking for associated lesions and (2) to guide the etiological diagnosis, especially when no molecular marker is available. Then, the type of liver siderosis (parenchymal, mesenchymal or mixed) and its distribution throughout the lobule and the liver are useful means for suggesting its etiology: HLA-linked hemochromatosis gene (HFE) hemochromatosis or other rare genetic hemochromatosis, nonhemochromatotic genetic iron overload (ferroportin disease, aceruloplasminemia), or iron overload secondary to excessive iron supply, inflammatory syndrome, noncirrhotic chronic liver diseases including dysmetabolic iron overload syndrome, cirrhosis, and blood disorders.

Interpreting liver iron MRI results

Diagn Interv Radiol. 2016 Jan; 22(1): 22–28.   Different forms of iron accumulation in the liver on MRI.  Idilman Is et al.  (Hacettepe University School of Medicine, Ankara, Turkey.)

Abstract

Magnetic resonance imaging (MRI) is a well-established imaging modality to evaluate increased iron deposition in the liver. Both standard liver imaging series with in-phase and out-of-phase T1-weighted sequences for visual detection, as well as advanced T2- and T2*-weighted measurements may be used for mapping the iron concentration. In this article, we describe different forms of liver iron accumulation (diffuse, heterogeneous, multinodular, focal, segmental, intralesional, periportal, and lobar) and hepatic iron sparing (focal, geographic and nodular). Focal iron sparing is characterized by hypointense areas on R2* map and hyperintense areas on T2* map. We also illustrate MRI findings of simultaneous hepatic iron and fat accumulation. Coexistence of iron (siderosis) and fat (steatosis) can make interpretation of in- and out-of-phase T1-weighted images difficult; calculation of proton density fat fraction and R2* maps can characterize abnormal signal changes observed on in- and out-of-phase images. Knowledge of different forms of hepatic iron overload and iron sparing and evaluation of T2* and R2* maps would allow correct diagnosis of iron-associated liver disorders

I can’t figure out how to private message you.  My hemoglobin and hematocrit have remained essentially normal. I wish it would let me take a pic of my papers and upload on here.  The biopsy ransom liver core biopsy benign liver tissue showing moderate iron deposition hemosiderosis grade 3 of 4. Negative for cirrhosis dysphasia or malignancy. It goes on to say portal regions show slightly increased fibrosis as noted on trichromatic stain. Portal regions also show scant lymphocytic infiltrates. Low power shows brownish cytoplasmic granules involving more than 90% of hepaticytes with apical accentuation bear the peripheral regions (chicken wire pattern). Also iron deposition within the lobular kupffer cells. If you wouldn’t mind messaging me your email I could send you pictures of some of my labs.  I know I don’t have hep b or c. I was not very kind to my liver through my twenties and I had a sister who died at age 33 of fatty changes in liver secondary to alcoholism  and pills.  My fear is that they didn’t get a part of the liver that may show more fibrosis or cirrhosis like you said and that my issue is potentially due to past alcohol use and the homozygous hemochromatosis is just pure coincidence 

Huge work, Gillian.  Jessica has struck gold with your responses.

Jessica, can you see the envelope beside Gillian's name?  That is what you click on.

 

Yes now I know.  Thanks