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Thursday, 22 November 2007

Treatment of genetic diseases in tha real world 8: Hemochromatosis

Disease characteristics. HFE-associated hereditary hemochromatosis (HFE-HHC) is characterized by inappropriately high absorption of iron by the gastrointestinal mucosa, resulting in excessive storage of iron particularly in the liver, skin, pancreas, heart, joints, and testes. Abdominal pain, weakness, lethargy, and weight loss are early symptoms. Without therapy, males may develop symptoms between age 40 and 60 years and females after menopause. Hepatic fibrosis or cirrhosis may occur in untreated individuals after age 40 years. Other findings in untreated individuals may include progressive increase in skin pigmentation, diabetes mellitus, congestive heart failure and/or arrhythmias, arthritis, and hypogonadism.--> -->This description applies to individuals with clinical expression of HFE-HHC. A large, but yet as undefined, fraction of homozygotes for HFE-HHC do not develop clinical symptoms (i.e., penetrance is low).

Diagnosis/testing. The diagnosis of HFE-HHC in individuals with clinical symptoms consistent with HFE-HHC and/or biochemical evidence of iron overload is typically based on the results of the screening tests transferrin-iron saturation and serum ferritin concentration, and of confirmatory tests such as molecular genetic testing for the p.C282Y and p.H63D mutations in the HFE gene and/or histologic assessment of hepatic iron stores on liver biopsy. A threshold transferrin-iron saturation of 45% may be more sensitive for detecting HFE-HHC than the higher values used in the past. Although serum ferritin concentration may increase progressively over time in untreated individuals with HFE-HHC, it is not specific for HFE-HHC and cannot be used alone for identification of individuals with HFE-HHC. About 87% of individuals of European origin with HFE-HHC are either homozygotes for the p.C282Y mutation or compound heterozygotes for the p.C282Y and p.H63D mutations.

Management. Evaluations at initial diagnosis: liver biopsy in individuals with serum ferritin concentration greater than 1000 ng/mL to determine if cirrhosis is present. Treatment of manifestations: There is no general agreement that phlebotomy (removal of blood) treatment is indicated in the presence of biochemically defined abnormalities (i.e., elevated transferrin-iron saturation and elevated serum ferritin concentration) and the absence of characteristic clinical endpoints (i.e., diabetes mellitus, cirrhosis, and liver carcinoma). Since the long-term clinical course appears benign in the majority of those who have abnormal laboratory tests only, phlebotomy may be deferred; biannual follow-up testing for increasingly abnormal serum ferritin concentration and transferrin-iron saturation levels is recommended. In the presence of characteristic clinical endpoints, treatment by phlebotomy is indicated to maintain serum ferritin concentration at 50 ng/mL or lower. If affected individuals are identified before hepatic cirrhosis develops and if total body iron depletion is successfully accomplished by therapeutic phlebotomy, life expectancy approaches normal.

Genetic counseling. HFE-HHC is inherited in an autosomal recessive manner. Usually the genetic risk to sibs of a proband of having HFE-HHC is 25%. However, the high carrier frequency for a mutant HFE allele in the general population of European origin (11% of the population, or 1/9 persons) means that on occasion one parent has two abnormal HFE alleles, usually in the absence of clinical findings. In such instances, the risk to each sib of a proband of being homozygous for HFE-HHC is 50%. Offspring of an individual with HFE-HHC inherit one mutant HFE allele from the affected parent. Because the chance that the other parent is a carrier for a mutant HFE allele is 1/9, the risk to the offspring of having HFE-HHC is about 5%. Although prenatal testing would be technically feasible when both parents carry identified HFE mutations, such requests would be highly unusual because HFE-HHC is an adult-onset, treatable disease and the homozygous p.C282Y mutation has low clinical penetrance.


1 comment:

praspowt said...


James C. Barton, M.D.
Southern Iron Disorders Center
Suite G-105
2022 Brookwood Medical Center Drive
Birmingham, AL 35209
The Basis of Therapeutic Phlebotomy (TP).
Hereditary hemochromatosis (HH), a common autosomal recessive disorder of Caucasians, is characterized by iron absorption in homozygotes wich is inappropriately great for the body iron content, and, in may subjects, is typified by progressive iron deposition in the liver, pancreas, heart, and other organs. TP, the first successful therapy for iron overload due to HH, is used to reduce body iron stores to minimal levels, and to maintain this state of iron balance for a lifetime. TP works by removing red blood cells which are rich in iron (200-250 mg of iron per unit of blood; 1 unit = 450-500 ml = "1 pint"). With TP, asymptomatic HH subjects can avoid irreversible tissue injury, and other patients can minimize the progression of symptomatic iron overload. Most HH patients are candidates for TP therapy, regardless of age, although a few, e.g., those with advanced hepatic cirrhosis and portal hypertension, may not tolerate TP well enough to permit "de-ironing". Despite attempts to develop more elegant strategies to remove iron from the body, TP is still the most effective, economical, and safe treatment known for iron overload due to HH. The degree of iron overload is assessed by measurement of the serum ferritin concentrations ([Ftn•) and by analysis of the liver biopsy specimen for iron. In practical terms, HH subjects with serum [Ftn] > 50 ng/ml or with increased liver iron content need TP.

The Rate of TP.
Initial "de-ironing" therapy may require many months in some cases, a few in others. Regardless of the degree of iron overload, however, the "de-ironing" must be accomplished as soon a feasible (preferably within 1 year). Typically, one unit of blood is removed weekly. Some individuals, especially males and those with larger body mass, tolerate the removal of two units per week. Many females, smaller persons, the elderly, and those with co-existing anemia or heart or pulmonary problems tolerate the removal of only 0.5 units/week. After a few units of initial TP, the bone marrow produces new red blood cells at a greater rate, permitting more blood to be removed more frequently. In unusual cases, stimulation of the developing red blood cells in the bone marrow by the hormone erythropoietin (taken by regular injection) facilitates the recovery of the red blood cells after TP. However, this is expensive therapy and is unnecessary for most patients . The red blood cells should be measured immediately before each TP (hemoglobin concentration = [Hb]; hematocrit = Hct). As a general rule, subjects undergoing TP whose values of [Hb] and Hct are less than 11.0 g/dL and 33%, respectively , are more likely to sustain undue fatigue and other immediate consequences of excessive blood removal and anemia. Further, TP is less effective in removing iron in these patients because of the reduced red blood cell content of the blood.

Helpful Hints about Blood Removal by TP.
TP should be performed by experienced medical, nurcing, or laboratory personnel, preferably under the direct supervision of the responsible physician. Hospitalization is rarely necessary. Patients should prepare themselves by being well-hydrated prior to TP, and planning their post-TP schedule to minimize vigorous psysical activity for 24 hours after TP. Blood should be removed using a 19- or 21-gauge needle ("butterfly"); a single venipuncture should suffice for [Hb] and Hct measurements and TP. Smaller needles are more comfortable for patients and preserve venous access better than the use of larger bore needles, and separate venipunctures for these [Hb] and Hct measurements and TP are unnecessary. Some persons with smaller veins have fewer problems with clotting in the TP needle when 1-2 asperin tablets are taken twice weekly. Occasionally, an indwelling venous access device for TP is necessary because of insufficient peripheral venous access. A written record of the [Hb] and the Hct values and volume (or weight) of blood removed with each TP session should maintained as part of the medical record. This permits quantification of the total amount of iron removed by TP.

Measuring and Maintaining Success of TP.
No formula accurately predicts the amount of TP necessary to achieve iron depletion. The progress of TP is monitored by periodic assessment of [Hb] and Hct values and their recovery rate, the size (MCV) of red blood cells, and the serum [Ftn]. Initial "de-ironing" should reduce the serum [Ftn]to < 20 ng/ml. Maintenance TP should be performed at intervals thereafter to maintain the serum [Ftn] < 50 ng/ml. Medicinal iron supplements should be avoided, but major dietary changes intended to minimize or avoid ingested iron are not usually necessary. Many patients and physicians monitor the serum iron concentration and transferrin saturation values after the the diagnosis of HH is established. These are not helpful indices of remaining iron stores, although the serum iron concentrations become normal and transferrin saturation values fall < 60% in many patients adequately treated with TP. Sustaining overt iron deficiency by excessive TP is not warrented.

The Benefits of TP.
The benefits of TP appear at various times in different subjects. Many patients with weakness and fatigue notice almost immediate alleviation of their symptoms early in the treatment course. Others do not regain their normal energy levels and sense of well-being for many weeks after "de-ironing" therapy is complete. Elevated hepatic enzymes levels, hepatomegaly, and right upper quadrant pain often take many months after "de-ironing" to resolve. Failure for this to occur should prompt an investigation for alternative explanations for the abnormal clinical findings. In patients with hepatic cirrhosis, TP has no apparent effect on the risk of developing primary liver cancer. Patients with arthralgias and minimal findings of arthropathy often improve with TP. The pain and progression of more severe arthropathy may be slowed by TP, but significant improvement in join function and deformity is uncommon. Occasional patients have exacerbation of joint pain during TP which resolves with iron depletion. Diabetes mellitus and other endocrinopathies are unlikely to improve greatly with TP, although hypogonadism of relatively recent onset sometimes abates with TP. Cardiac complications due to iron deposition in heart muskle or in the cardiac conducting systen often improve dramatically with aggressive TP. However, coronary artery disease is a common accompaniment of cardiac abnormalities in older patients and is unaffected by TP. The dark skin discoloration of iron overload gradually fades as "de-ironing" with TP nears completion. TP is never a substitute for appropriate management of hepatic cirrhosis or other liver disease, diabetes mellitus and other endocrine abnormalities, arthropathy, and cardiac abnormalities. Altogether, patients without hepatic cirrhosis or diabetes mellitus who undergo and maintain iron depletion by TP have a statistically normal life expectancy. Recent evidence suggests that HH subjects diagnosed early in life and treated with TP for health maintenance could experience a decreased rate and/or severity of coronary artery atherosclerosis and/or malignancy, although this is unproven. Even in patients with hepatic cirrhosis or diabetes mellitus, TP significantly improves the quality of life in many patients, and may yield some longevity benefits.

Disposal of TP blood
The disposal of blood removed by TP concerns many HH patients and health care personnel, and many believe that most, if not all, of this blood is suitable for transfusion. Because approximately 1 in 200 apparently healthy individuals who volunteer as blood donors (unknowingly) have HH, it is known that blood from HH subjects is being used for transfusion on a regular basis. Further, blood banking statutes and practice sometimes coincide with HH experts such that selected HH patients can donate their TP blood to the community blood supply. However, maintaining a high quality of blood for transfusion causes the rejection of many donors: those beyond certain age limits (usually < 18 years and > 60 years), those with diabetes mellitus, elevated hepatic enzyme concentrations, cardiac disorders, excess ethanol intake, or viral hepatitis, those using certain medications, and those who have donated blood (or been treated by TP) within 6 weeks. Some HH patients are geographically situated such that utilization of their TP blood for transfusion is not possible. Most blood procurement organisations do not deliver therapy (TP, in this case), and do not have adequate resources to monitor TP (and other) treatments required by many HH patients). Thus, diverse factors commonly encountered in HH exclude many patients from being transfusion donors. Alternatively, HH blood obtained by TP can sometimes be used for medical research projects. However, it is mandatory that approval of such projects be obtained through institutional review boards for human use, that donors be adequately informed of the anticipated use of their blood and the possible consequences of the research, and that the research outcomes not be prejudiced by possible differences in the blood of HH subjects and otherwise normal individuals (especially with regard to studies involving human leukocyte antigen (HLA) immunophenotypes of DNA). TP blood not suitable for the above purposes must be discarded according to current regulations for body fluids and other medical waste.