Hemochromatosis

Merck 18^th Ed, p 1131

80% genetic caused by mutation of the HFE gene, homozygous for C282Y or C282Y/H63Dcompound heterozygote mutation.  Testing for these genes identifies > 95 of cases. The disorder is autosomal recessive with a homozygous frequency of 1:200 and a heterozygous frequency of 1:8 in Northern Europeans.  It is uncommon in blacks and Asians.  The mechanism for iron overload is increased iron absorption from the GI tract.  Total body iron content can reach as high as 50g, normal is 2.5 in women and 3.5 in men.  Iron deposition in organs catalyzes generation of reactive free hydroxyl radicals. 

Symptoms are uncommon before middle age.  Of affected men 80-90% have total iron stores >19g before symptoms develop.  Because iron accumulates in multiple sites, symptoms can occur in many organs. In men, cirrhosis or diabetes is often the initial presentation.  Hypogonadism is common in both sexes as and may predate other manifestations.  Liver disease is the most common complication, and about 20-30% progress further to hepatocellular carcinoma.  10-15% of untreated patients develop heart failure; 90% excessive skin pigmentation; 65% diabetes and its sequelae (nephropathy, retinopathy, neuropathy); and 25-50% arthropathy (joint problems).  One large study showed that of those at diagnosis, 22% had cirrhosis of the liver (Conn’s below). 

Diagnosis:  Serum iron increased (> 300 mg/dl).  Serum transferrin saturation is usually >50% and often >90%.  Serum ferritin is increased.  Gene assay establishes the diagnosis.  Hepatic iron content can be estimated with a high intensity MRI.  Because of cirrhosis markedly affects prognosis, a liver bioposy is done if serum ferritin is 1,000. 

Phlebotomy is the simplest method of excess iron removal.  It prolongs survival but does not prevent hepatocellular carcinoma.  Standard treatment about 500 mL/wk of blood (about 250 mg of iron) is removed weekly until serum iron levels are normal and transferring saturation is <50%.  Weekly phlebotomy may be needed for several years. 

{My father underwent blood letting when in his fifties.  He told me his blood was too thick.  I recall his blood being abnormally bright red and his complexion ruddy.  Very fair skin, and exceptionally quick at getting sunburned.  He possibly also had Waardenburg syndrome.}   

Diabetes occurs through accumulation in pancreas.

MRI algorithms reduce the necessity of a liver biopsy

Serum iron .300mg/dL; serum transferring saturation is usually >50% and often .90%.  Because cirrhosis markedly affects prognosis, al liver biopsy is done if serum ferritin is unexpectedly high (>1000, but adjusted for age).  When iron levels are normal, further phlebotomy can be performed to maintain transferring saturation at > 30%.    

Conn’s Current Therapy

(additional information)

In a study of 410 homozygotes from Canada and France, 22% had cirrhosis of the liver at the time of diagnosis.  It seems that there are other factors other than iron overload that contribute to cirrhosis.  The effect of iron depletion therapy has usually stabilized liver disease.  The other common clinical manifestations are arthralgias, pigmentation, diabetes, congestive heart failure, impotence, and fatigue.  Rate of 1/200 in whites.  It usually goes undiagnosed. 

An elevated transferring saturation has a sensitivity of greater than 90%.  The unsaturated iron-binding capacity is a one-step colorimetric assay.  It is an inexpensive test compared with transferring saturation.  The relationship between serum ferritin and total body iron stores has been clearly established by strong correlations with hepatic iron concentration and amount of iron removed by venesection.  However, ferritin can be elevated by secondary to chronic inflammation and histolytic neoplasm.  Other causes include alcoholic liver disease, chronic viral hepatitis, and nonalcoholic steatohepatitis.  Patients with cirrhosis have a 5.5-fold relative risk of death compared with noncirrhotic hemochromatosis patients.   . 

A first step is the measure of transferring saturation, the protein which chemically binds to iron and carries it through the blood to the liver, spleen and bone marrow.  Saturation level above 45% is probably a good cutoff to determine whether a patient is a candidate for further testing.  Carriers of the disease may never manifest the symptoms. 

Wikipedia.org

Standard Diagnosis measures for hemochromatosis, serum transferring saturation and serum ferritin tests is recommended if the patient has a parent, child or sibling with the disease, or have any of the following symptoms are signs:  joint disease, severe fatigue, heart disease, elevated liver enzymes, impotence, diabetes. 

Abnormal iron regulatory genes do not reduce their absorption of iron in response to increased iron levels in the body.  Stored mainly as ferritin, it is deposited in organs as hemosiderin, and this is toxic to tissue, probably at least partially by inducing oxidative stress.  Iron is a pro-oxidant; thus hemochromatosis shares common symptomology with other pro-oxidant diseases such as Wilson’s disease, chronic manganese poisoning, and hyperuricemic syndrome in Dalmatian dogs.  In hemochromatosis the enterocyte in the small bowels are somehow constantly responds as though there is an iron shortage, and as a consequence, over-express the necessary channel proteins resulting in unnecessary iron absorption.  Iron is stored in the liver, heart and pancreas.  Nearly one-third of people with hemochromatosis and cirrhosis eventually develop liver cancer.