Dr.Barry Kelleher and Dr.John Crowe say hereditary haemochromatosis is the most common cause of iron overload, and the highest frequency in the world has been identified in Ireland.
Disorders of iron metabolism, particularly of iron deficiency, arre well recognized throughout the world.
However with increasing affluence in the Western World , diseases associated with iron overload are becoming a greater health burden. Hereditary haemochromatosis (HH) is the commonest cause worldwide and also the best characterized.
The first description of the disease was by Trousseau in 1865 when he described the clinical triad of glycourea, hepatic cirrhosis and hyper-pigmentation of the skin. Von Recklinghausen recognied that these features were caused by excessive iron deposition and coined the term haemochromatosis 25 years later. Since these original descriptions, HH has been recognized as an autosonal recessive condition defined in 2000 by the European Association for the Study of the Liver (EASL) in its consensus statement as" an inherited disorder resulting from an inborn error of iron metabolism which leads to progressive iron loading of parenchymal cells in the liver, pancreas and heart. In its fully developed stage , organ structure and function are impaired."

Genetic aspects
Two genetic mutations of the haemochromatosis gene (HFE) were discovered by Feder et al . in 1996 - C282Y and H63D. Iron overload is associated with C282Y homozgosity and to a lesser extent with C282Y/H63D compound heterozygosity.
How these mutations precipitate iron overloading is not fully understood but it is known that they cause a structural change within the HFE protein. This is postulated to result in failure of the duodenal enterocyte to recognize that circulating iron stores are adequate and subsequently in upregulation of its iron absorbtive capacity. Previous population screening studies have consistently shown a very high prevelance of haemochromatosis of between 1 in 300 and I in 400 in Caucasian populations.
With the advent of genetic testing , the numbers with susceptibility to iron overload are even greater than expected. It is no surprize, due to the genetic homoheneity of the Irsh population and their Celtic origin, that the highest frequency of C282Y alleles worldwide has been reported in the Irish population.
Results recently published reveal that 1: 83 of the population are C282Y homozygous, 1:25 are C282Y/H63D compound heterozygous and 1: 5 are C282Y heterozygous i.e. 1: 20 of the Irish population, have the genetic susceptibility to develop significant iron overload.

Presentation
In general, the severity of the clinical illness is related to the iron burden. The clinical condition evolves in a series of stages beginning with

* clinically insignificant iron accumulation (0-20 years/O-5g iron storage).
* iron overload without disease (approximately 20-40 yers/ 10-20g iron storage)
*iron overload with organ damage (greater than 40 yeare/ greater than 20g iron storage).

Fatigue is the commonest symptom affecting up to 60% of patients but is often associated with degrees of iron overload below the threshold fo organ damage.The remaining common symptoms and signs in the developed syndrome are as follows:

1. Sexual dysfunction (10-40 per cent).
2. Arthralgias/arthritis 30-40 per cent).
3. Hepatomegaly /cirrhosis (22-60 per cent).
4. Diabetis mellitus (10-30 percent).
5. Cardiac failure (15-35 per cent).

The outline above suggesting simple step-wise progression of iron overload overlooks one of the most frustrating aspects of dealing with this disease- that of phenotypic variability.. Of those that are C282Y homozygous, approximately 60 per cent will develop iron overload sufficient to cause organ damage and reports suggest that figure is between 2-20 percent in C282y/H63D compound heterozygotes. The remainder, despite their genetic predisposition to excessive iron loading will not accumulate iron sufficient to cause end organ damage.
The factors that influence this variability are incompletely understood.Menstrual blood loss is one well recognized contributing factor but other enviornmental influences such as diet and alcohol contribute to the severity of disease prresentation. However, these factors do not fully explain the wide spectrum of disease manifestations and it is felt that mutations of other iron transport ,as yet unidentified, may contribute.

Diagnosis
The diagnosis of HH is based on biochemical evidence of irnoverload, viz. high fasting serum iron , a positive genetic gest and where indicated liver histology.
Our recommendations for the Irish population are as recommended by the practice guidelines of the American Association for the Study of Liver Disease (AASLD).

SYMPTOMATIC Unexplained manifestations of liver disease indices Type 11 diabetes mellitus Atypical cardiac disease Early onset sexual dysfunction Early onset atypical arthropathy

ASYMPTOMATIC Individuals with unexplained elevation of iron Unexplained elevation of liver enzymes

Recommendations Fasting transferrin saturation (TS) and serum ferritin +ve TS > 45% * / ferritin elevated Genotype testing FAMILY SCREENING Recommendations First degree relative of confirmed case of confirmed case of HH Direct genotype testing ____________________ Children of confirmed case of HH Genetic testing of the spouse:- If negative no need to screen children: If carrier (C282Y or H63D) further genetic testing of children is indicated in those aged > 20 * Transferrin saturation may be unreliable if there has been recent blood loss.

Caution with respect to use of widespread screening , amongst extended families, in particular young children, is warrented. The potential impact of genetic discrimination and needless anxiety in th paediatric population should be avoided. Given the fact that there is no disease impact in young patients, we advocate screening of adults only when each individual can consent for the test and take responsibility for its result.
Prioe to the commencment of therapeutic phlebotomy, some patients may require liver biopsy to estimate the degree of fibrosis or cirrhosis.The presence of cirrhosis statifies those at risk from complications of chronic liver disease (varices, ascites ) but, more importantly , highlights those at rish from hepatocellular carcinoma. Due to the invasive nature of the procedure, biops is recommended for those likely to have significant hapatic damage. This can be predicted from the presence of one or more of the following clinical/biochemical factors:

* age greater than 40
* abnormal transaminases
*Ferritin greater than 1000

Discretion is appropriate in recommending liver biopsy on the basis of age alone. In the absence oif the above indications of cirrhosis, other risk factors ( alcohol abuse or coexisting clinical features of HH ) may play a role in making this recommendation.

Treatment
Phlebotomy is the cornerstone of treatment and, given its simplicity, is likely to remain so for the foreseeable future. Certain clinical features may be ameliarated by phlebotomy (malais, fatigue, skin pigmentation, insulin requirements, abdominal pain)., whereas other features are either less responsive to iron removal or do not respond at all ( arthropothy, hypogonadism, cirrhosis).
Therapeutic phlebotomy of 400-500ml once or twice a week as tolerated. Each venisection should be preceded by measurement of haemoglobin to avoid iatrogenic anaemia. Ferratin is a reliable indicator during therapeutic phlebotomy and once patients are nearing iron depletion, a goal of serum ferritin less than 50 mg/l
indicated iron depletion.
Maintenance phlebotomy must be tailored for each patient by six monthly monitoring of fasting serum transferrin and ferritin levels.The factors that influence aggressive loading following iron depletion are not fully understood but phlebotomy therapy itself, by stimulating erythropoiesis is felt to contribute to increasing iron absorption.
Strict iron deficient diet is not recommended but iron rich foods sgould be avoided or consumed in modertion. Iron and Vitamin C supplements should be avoided. Tea drinking is benificial but to make significant impact,large volumes must be consumed, although in a nation of tea drinkers this is often achieved without effort.
trreatment must also include surveillance for hepatocellular carcinoma (HHC). HH patients with cirrhosis have the highest relative risk of HHC known (>200 ) and in early reports, before surveillance was commonplace, it was responsible for about 30 per cent of HH deaths.
Despite these figures there are no data on the optimal method, frequency or cost effectiveness for surveillance of HHC. In light of thism most institutions advocate what is practical and we rrecommend annual liver ultrasound and estimation of serum alpha-feta-protein levels every six months. Surveillance in those without cirrhosis is not warrented but in light of several reports of HHC in this cohort, extra vigilance does seem prudent.

Screening
No other aspect of HH is more hotly debated than the question of screening. The central question relates to whether the benefits of screening outweigh the costs to a sufficient degree to justify general screening on public health grounds.The general principles of screening for any disease within a population must be considered. In Ireland, for example, HH is common (five per cent of population is genetically predisposed) , easily treated and can be deteted at a preclinical stage, suggesting that it may be an ideal candidate for population screening.
Arguements against highlight the unpredictable course in many and the prohibitive cost benefit. As the costs of genetic testing continue to fall, the likelihood of population screening in areas of increased prevalence of the specific mutations is high.

Future directions
Research in the area of iron metabolism has exploded since the discovery of the gene in 1996 but, as with many discoveries, it has opened the door on many as yet unanswered questions. Areas of active research include

* identification of major and minor disease modifiers
*determine the effect of C282Y and H63D mutations in

contributing to other liver diseases

*The contribution of HH to the diabetic health burden
*the most effective method of population screening.

References are availavle on request.
Dr. Barry Kelleher MB MRCPI Registrar in Gastroenterology,
Dr.John Crowe, Ph.D. FRCPI, Consultant Gastroenterologist/Hepatologist,Centre for Liver Disease, Mater Miseracordiae Hospital,Dublin 7.