Juvenile Hemochromatosis

Excerpt

Clinical characteristics: Juvenile hemochromatosis is characterized by onset of severe iron overload occurring typically in the first to third decades of life. Males and females are equally affected. Prominent clinical features include hypogonadotropic hypogonadism, cardiomyopathy, glucose intolerance and diabetes, arthropathy, and liver fibrosis or cirrhosis. Hepatocellular cancer has been reported occasionally. The main cause of death is cardiac disease. If juvenile hemochromatosis is detected early enough and if blood is removed regularly through the process of phlebotomy to achieve iron depletion, morbidity and mortality are greatly reduced.

Diagnosis/testing: The diagnosis of juvenile hemochromatosis is established in a proband with clinical and laboratory features of iron overload by identification of biallelic pathogenic variants in HAMP or HJV on molecular genetic testing. Individuals with suggestive features of juvenile hemochromatosis who do not have biallelic HAMP or HJV pathogenic variants identified on molecular genetic testing should have further evaluation by imaging and/or liver biopsy.

Management: Treatment of manifestations: Phlebotomy for treatment of iron overload as for HFE hemochromatosis: phlebotomy of 1 unit of blood (~200 mg of iron) 1x/week for up to 2-3 years to reduce iron stores to desired levels (serum ferritin concentration ~50 ng/mL), followed by phlebotomies to maintain normal serum iron levels. Conventional treatment of secondary complications including hypogonadotropic hypogonadism, arthropathy, cardiac failure, liver disease, and diabetes mellitus as indicated. Hypogonadism is treated with testosterone replacement in males and cyclical estrogen and progesterone therapy in fertile females. Arthropathy is treated with analgesics and NSAIDs. Cardiac failure and arrhythmias require treatment as per cardiologist. Glucose intolerance or diabetes may require oral agents or insulin administration.

Prevention of primary manifestations: Individuals with biochemical evidence of iron overload but without evidence of organ dysfunction or failure should be encouraged to undergo regular phlebotomies until excess iron stores are depleted to prevent the development of complications associated with excess iron stores.

Prevention of secondary complications: Hormone replacement therapy may prevent osteoporosis.

Surveillance: Monitor those at risk with annual measurement of serum ferritin concentration and transferrin saturation starting in early childhood. For individuals with iron overload: serum ferritin every 4-8 phlebotomies during the induction phase; every 1-2 phlebotomies as ferritin levels approach the target of 50 ng/mL; liver function tests and fibroelastography every 6-24 months according to severity of liver dysfunction; abdominal ultrasound and serum alpha-fetoprotein concentration every 6 months in those with severe fibrosis or cirrhosis to monitor for hepatocellular cancer; cardiac ultrasound and MR-based quantitation of iron according to the severity of cardiac dysfunction; Holter EKG as needed to evaluate for arrhythmias; serum FSH, LH, and testosterone or estradiol every 12 months or as needed; fasting and postprandial serum glucose and Hgb A1c every 6-12 months according to needs; vitamin D, PTH, serum and urinary calcium and phosphorus, C-terminal telopeptide every 12 months according to needs; DXA every 24 months or as needed.

Agents/circumstances to avoid: Alcohol consumption; ingestion of iron-containing preparations and supplemental vitamin C; handling or eating uncooked shellfish or marine fish because of risk of fatal septicemia from the marine bacterium V vulnificus.

Evaluation of relatives at risk: It is appropriate to clarify the clinical/genetic status of all at-risk family members (i.e., sibs) of an affected individual in order to identify as early as possible those who would benefit from early monitoring for the development of iron overload. If juvenile hemochromatosis is detected before evidence of organ damage, treatment via phlebotomy can reverse or prevent many of the secondary complications resulting from organ damage. Evaluation can include serum iron indices (i.e., serum iron, transferrin saturation, and serum ferritin), serum transaminases, C-reactive protein, and molecular genetic testing in relatives at risk before evidence of organ damage from iron overload.

Genetic counseling: Juvenile hemochromatosis is inherited in an autosomal recessive manner. If each parent is known to be heterozygous for a HAMP or HJV pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an unaffected carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing are possible if both pathogenic variants in the family have been identified.