We just discovered that Dr Whitington has just had another article published:

Whitington, P.F & Padmini, M, 2005, “Neonatal Hemochromatosis: Is It an Alloimmune Disease?”, Journal of Pediatric Gastroenterology and Nutrition, Vol 40 pp 544- 549, May 2005

Unfortunately there’s no abstract available on the internet.  So I’d recommend accessing the article through your doctor.  To date it’s the most useful paper I’ve read, so here’s my attempt to summarise what it says (along with a few explanatory comments of my own).

What is neonatal hemochromatosis (NH)?

  • NH is a severe neonatal liver disease associated with iron deposition and resulting damage in other organs and tissues.
  • NH has similar characteristics to hereditary hemochromatosis
  • NH is considered a rare disease

What causes NH?

  • Causes are still unknown.
  • Some have suggested it’s a syndrome where a number of factors (infection, genetic-metabolic disease, and toxic insult) all lead to the same outcome or characteristics.
  • Is it genetic? The article argues that the evidence suggests not.  The reoccurrence rate of the disease once it has appeared in one child is around 80%.  This is much higher than recurrence rates associated with recessive autosomal inheritance (the common genetic inheritance process).  In addition the disease hasn’t been observed to reoccur in family trees.
  • Is it caused by infection? There is no known infectious disease that can recurrently generate the characteristics of NH.

So… the evidence led the authors to hypothesise that NH could be an alloimmune disease.  That is, a disease where the mother’s immune system generates antibodies against fetus antigens resulting in damage to the fetus.

How does an alloimmune disease cause fetal problems?
The mother generates antibodies against fetal antigens (an antigen is simply a molecule that stimulates the immune system to produce antibodies and could be any type of protein).  There are a number of mechanisms by which damage is done to the fetus when the mother’s antibodies attack the fetal antigens.

There are four classes of antibodies.  Only the immunoglobulin G (IgG) class are transported across the placenta to the fetus.  These antibodies (the IgG) provide the fetus with protection against antigens to which the fetus has not yet been exposed.  So IgG is the way that the mother helps give the fetus’ immune system a kick start.  In the case of pregnancy, alloimmune disease represents a failure of the mother’s IgG (antibodies) to recognise and respond to fetal proteins (the antigens).

Other known alloimmune diseases are hydrops fetalis and alloimmune thrombocytopenia.

How does the intravenous immunoglobulin treatment help?
The paper describes a treatment protocol for administering intravenous immunoglobulin to mothers.  The treatment protocol is a dose of 1g/kg each week (if you weigh 70kg, you’ll receive a 70g dose).   This dose is based on treatment for Rh incompatibility.

The treatment starts at week 18, since this is when active transport of IgG across the placenta starts.

It is thought that the IgG treatment potentially works via one of three mechanisms:

  1. blunting the maternal immune response;
  2. flooding the placental transport pathway with “good” antibodies.
  3. nonspecific antibody binding limiting the number of “bad” antibodies binding to the fetal antigens

How successful has the IgG treatment protocol been?
The treatment has been used to treat 18 women through 22 pregnancies, whose most recent pregnancy had resulted in NH. Normally the disease recurs at a rate of 80% and in the vast majority of cases NH is fatal without liver transplant.

To date all 22 babies have survived!  However, 6 babies showed evidence of liver disease, and there was other evidence that the majority of the babies (17) were affected with NH.

When analysed the treatment protocol is positively correlated with improved infant survival (p=0.0009!)  The paper therefore concludes that the treatment modifies NH so that it is no longer lethal and that the results provide evidence supporting their alloimmune disease hypothesis.

Where is the research heading in the future?
The authors hypothesise that a fetal liver protein associated with iron control is the antigen that is targeted by the mother’s antibodies.

Blood samples and analysis from women in the treatment program have identified some evidence to support this hypothesis.  However the exact nature and role of the protein is yet to be determined.  Identitying and understanding this protein is the next step.

It is hoped that if the protein can be identified blood tests can be developed to diagnose NH in mothers and also help streamline preventative treatments.