Of*Department of Internal Medicine, Ascension St. John Hospital, Detroit, MI
†Department of Pediatrics, Ascension St. John Children's Hospital, Detroit, MI
‡Michigan State University College of Human Medicine, East Lansing, MI
§Department of Pediatric Gastroenterology, Ascension St. Children's Hospital. John, Detroit, MI
∥Division of Pediatric Hematology Oncology, Children's Hospital of Michigan, Detroit, MI
¶Central Michigan University School of Medicine, Detroit, MI.
Received February 17, 2022, accepted May 14, 2022.
The authors inform that they have no funding or conflict of interest.
Informed consent was obtained from the patient's guardian for the publication of this case.
The case was not presented at previous meetings.
Correspondence: Bola Nashed, MD, 304 Shore Club Dr, St Clair Shores, MI 48080. Department of Internal Medicine, Ascension St. John Hospital, Detroit, MI Email:[email protected].
This is an open access article distributed under theCreative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided proper attribution is given to the original work.
juvenile hemochromatosis(JH), also known as hereditary hemochromatosis type 2, is a rare and severe autosomal recessive disease manifested byiron overloadand has an aggressive clinical course (1). The hemozuvelin (HJV) gene encodes hemozuvelin, which regulates the production of hepcidin. Its mutations represent more than 90% of JH cases. the p.Gly320Val variant is the most prevalent pathogenic variant reported to date (2). Hepcidin inhibits the release of iron from enterocytes and macrophages into the circulation (1). The absence of HJV activity leads to defective hepcidin production, resulting in circulatory disturbances.iron overload. This results in the deposition of excess iron in the tissues leading to organ damage (3).
One of the most serious sequelae of JH is eventual liver disease.cirrhosis, which has been associated with reduced life expectancy unless treated early. Other possible serious complications include cardiomyopathy, hypogonadotropic hypogonadism, diabetes, and arthropathy.3).
A 9-year-old boy presented to our pediatric gastroenterology clinic for evaluation of elevated transaminase levels (AST61IU/L, ALT110IU/L) found incidentally as part of the evaluation for cervical lymphadenopathy. Laboratory tests were obtained before any treatment, and the lymphadenopathy resolved after a short course of antibiotics. He had a history of asthma and was taking montelukast and budesonide with no additional comorbidities. Physical examination revealed a thin boy with a BMI in the 18th percentile but otherwise without complications. Laboratory studies for infectious etiologies, Wilson's disease, alpha-1-antitrypsin deficiency, fatty liver disease, and autoimmune hepatitis were normal. Repeated liver enzyme tests four months later showed persistently elevated transaminase levels despite a normal liver ultrasound. To rule out possible drug-induced liver injury, montelukast was discontinued, but transaminase levels remained elevated (AST 91 IU/L, ALT 121 IU/L). All other tests, including alkaline phosphatase, γ-glutamyl transferase, total bilirubin, and albumin were normal. An iron panel revealed elevated ferritin (1367 ng/mL), serum iron (273 μg/dL), TIBC (290 μg/dL), iron saturation (94.1%), and serum transferrin (229 μg/dL). These results suggest circulationiron overloadTherefore, a genetic panel for hemochromatosis was obtained that showed double heterozygosity for two pathogenic mutations in the HJV gene (p.Leu366* in exon 4 and p.Asp149Thrfs*97 in exon 3), confirming the diagnosis of JH. Both parents were confirmed carriers of each HJV variant mutation.
MRI of the liver showed mild hepatomegaly (range 15 cm), diffusely low T2 signal, and liver iron concentration between 14.46 and 19.13 mg iron/g dry liver (normal range 0.2 to 2 mg iron/g dry liver). Liver fibrosis showed grade F0-1 fibrosis and grade S1 steatosis. In the absence of clinical and laboratory signs ofcirrhosis, and significant evidence of fibrosis on liver elastography, we opted not to perform a liver biopsy.
The electrocardiogram and echocardiogram were normal. Cardiac MRI showed normal structure and function. The cardiac T2 value was estimated to be 40 to 49 ms (normal range >20 ms), reflecting no significant cardiac changes.iron overload. Brain MRI revealed T1 hyperintensity involving bilateral globus pallidus, internal capsule, ventral thalamus and also showed intrinsic T1 hyperintensity of the ventral aspect of the anterior pituitary associated withiron overload. He was referred to a pediatric endocrinologist who found normal endocrine function. Hematology is established weekly.phlebotomytreatment. From the start of the treatments, he had a gradual decrease in inferritin levels (Fig. 1) and after 6 months, he had a marked improvement in iron deposition (hepatic iron concentration decreased to 5.3 mg iron /g dry weight of liver). Continue less aggressivephlebotomytreatment as your serum ferritin levels approach the normal range.
Because the presentation of JH varies according to its severityiron overload, can easily be overlooked. Nonspecific symptoms such as fatigue and decreased appetite usually precede the development of organ dysfunction. Liver involvement can manifest as asymptomatic elevation of liver enzymes, hepatomegaly, liver fibrosis (44%-58% of cases),cirrhosis(27%-42% of cases), and rarely hepatocellular carcinoma. Iron deposition in the anterior pituitary can lead to hypogonadotropic hypogonadism (67-91% of cases) and diabetes (30-57% of cases) due to pancreatic fibrosis. Heart disease, including arrhythmias and cardiomyopathy (35-37% of cases), is the most common cause of death. Iron deposition in the joints can cause arthralgia, which usually affects the metacarpophalangeal joints. Increased skin pigmentation is observed in 24% of cases (2).
A ferritin level above the normal range for age and sex and a transferrin saturation >45% in a patient without acute inflammation suggests hemochromatosis. Diagnosis is confirmed by genetic testing (2). After confirmation, the extent of involvement of other agencies should be determined (4).
Phlebotomyis the preferred treatment. Iron chelating agents, including deferasirox, may be used ifphlebotomyis contraindicated Patients with severeiron overloadmay require both treatments.Phlebotomycan be performed weekly in the induction phase with a target ferritin level of approximately 50 μg/L (5), after whichphlebotomydone less frequently to maintain normal ferritin and transferrin saturation levels (6). EarlyphlebotomyTreatment may stop the progression of organ damage, but depending on the severity, it may not completely reverse organ dysfunction (2).
The diagnosis and management of JH is essential to optimize patient outcomes. We recommend obtaining ferritin and transferrin levels for patients with signs of hepatocellular injury without a clear explanation. Clinicians should also recognize unexplained cardiac or endocrine dysfunction as possible early markers of JH. Genetic testing must be done to confirm the diagnosis, and MRI studies are important to assess the extent of iron deposition.Phlebotomyis the primary therapeutic approach. Although JH is extremely rare, clinicians should keep it in their differential diagnosis because early treatment can prevent complications and end-organ damage.
Dr. Nashed (author of the article) participated in the design and review of the literature. Dr. Fonseca and Dr. Vander Pols participated in the design and review of the literature. Dr. Kumar, Dr. Lyons, Dr. Berman, and Dr. Guzzardo participated in draft review and approval for submission.
1. Griffiths WJH, Besser M, Bowden DJ, et al. Juvenile hemochromatosis. Lancet Child Adolesc Health. 2021? 5:524-530.
- listing here|
- Academic Google
2.Piperno A, Bertola F, Bentivegna A.juvenile hemochromatosis. February 17, 2005 [Updated January 9, 2020]. In: Adam MP, Mirza GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington; 1993-2022
- listing here
3. Kong X, Xie L, Zhu H, et al. Genotypic and phenotypic spectra of hemojuvelin mutations in patients with primary hemochromatosis: a systematic review. Dis. rare from Orphanet J. 2019? 14:171.
- listing here|
- Academic Google
4. Bacon BR, Adams PC, Kowdley KV, et al.; American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline from the American Association for the Study of Liver Diseases. hepatology. 2011? 54:328-343.
5. Adams PC, Barton JC. How do I treat hemochromatosis? Blood. 2010? 116:317-325.
juvenile hemochromatosis;increased transaminases;phlebotomy;cirrhosis;iron overload
If left untreated, juvenile hemochromatosis can cause serious, life-threatening complications. The symptoms of juvenile hemochromatosis usually become apparent at some point before 30 years of age. However, in rare cases, some individuals have not developed symptoms until their 30s.How rare is juvenile hemochromatosis? ›
Prevalence. Juvenile hemochromatosis is rare; global HJV pathogenic allele frequency has been estimated at 0.000316-0.00074 [Wallace & Subramaniam 2016]. Affected individuals have been reported worldwide.What is the average age of diagnosis of hemochromatosis? ›
Men with type 1 or type 4 hemochromatosis typically develop symptoms between the ages of 40 and 60, and women usually develop symptoms after menopause. Type 2 hemochromatosis is known as a juvenile-onset disorder because symptoms often begin in childhood.Can a child get hemochromatosis? ›
Hereditary hemochromatosis is a genetic condition. For kids to get it, both of their parents must have the gene that causes the condition. But many kids who inherit the gene from their parents do not develop any problems. They may absorb and store extra iron, but not enough to cause health problems.How quickly does hemochromatosis progress? ›
Iron accumulation in classic hereditary hemochromatosis occurs slowly over many years. Eventually, iron accumulation causes tissue damage and impaired functioning of affected organs. In many affected individuals, symptoms may not become apparent until some point between 40-60 years of age.Is hemochromatosis a form of leukemia? ›
Hemochromatosis is a blood disorder, not cancer. However, certain complications, including cirrhosis, can lead to cancer. Receiving care from an experienced program such as ours can lower the risk.Can hemochromatosis be asymptomatic? ›
Men with hereditary hemochromatosis are more likely to develop complications and often at an earlier age. An estimated 9% (about 1 in 10) of men with hereditary hemochromatosis will develop severe liver disease. However, most people with hereditary hemochromatosis never develop symptoms or complications.Can you lead a normal life with hemochromatosis? ›
If not caught and addressed early, severe hemochromatosis can cause serious problems. These complications can include organ damage and possible death. But hemochromatosis is also a manageable disease. With early detection and treatment, you can survive and live a normal, healthy life.What are the behavioral problems of hemochromatosis? ›
Early symptoms may include lethargy and weakness, irritability, depression, joint pain, yellowish skin, and loss of body hair. Regular treatment with phlebotomy or chelation therapy is needed to reduce iron levels.What confirms hemochromatosis? ›
Doctors usually order blood tests to check for the gene mutations link that cause hemochromatosis. Finding two copies of the HFE link gene with the C282Y mutation confirms the diagnosis of primary hemochromatosis. Doctors usually order blood tests to check for the gene mutations that cause hemochromatosis.
This is a rare inherited condition that affects teens and young adults ages 15 to 30.
Hemochromatosis is listed in the Social Security Administration's (SSA) Blue Book (the impairment listing manual) as one of the conditions that may potentially qualify a claimant for Social Security Disability Insurance or Supplemental Security Income.How do you know if your child has hemochromatosis? ›
Hemochromatosis Symptoms in Infants and Children
Abdominal pain. Weakness. Skin color changes (may be gray, brown, or bronze) Edema, or swelling caused by a buildup of fluids in the body.
You're only at risk of haemochromatosis if you inherit the faulty HFE gene from both of your parents. If you only inherit the faulty gene from 1 parent, you'll be at risk of passing it on to your children – known as being a "carrier" – but you will not develop haemochromatosis yourself.What are the types of hemochromatosis in children? ›
Genetics. Juvenile hemochromatosis can be caused by inheriting two mutated copies (alleles), one from each parent, of the genes for the proteins hemojuvelin (HFE2/HJV) or hepcidin (HAMP), and the disease can be subdivided into hemochromatosis types 2A and 2B according to which gene/protein is affected.What is Stage 1 of hemochromatosis? ›
Early symptoms of Hemochromatosis type 1 can include fatigue, weakness, and joint pain. Other symptoms may include abdominal pain, loss of sex drive, liver disease, diabetes, heart problems, and skin discoloration. Hemochromatosis type 1 is the most common type of hemochromatosis, and it affects more men than women.What is mild hemochromatosis? ›
Hemochromatosis is a disorder in which extra iron builds up in the body to harmful levels. Without treatment, hemochromatosis can cause iron overload, a buildup of iron that can damage many parts of the body, including your liver, heart, pancreas, endocrine glands, and joints.Are you always tired with hemochromatosis? ›
Initial symptoms of haemochromatosis can include: feeling very tired all the time (fatigue) brain fog, mood swings, depression and anxiety. weight loss.What cancers are associated with hemochromatosis? ›
Risks associated with hereditary hemochromatosis
HH patients are at an increased risk of developing liver damage and liver cancer, particularly a type called hepatocellular carcinoma.
The name Ferroportin Disease (FD) refers to a clinical entity that differs from all other known forms of hereditary iron overload, including hemochromatosis (HC) [synonymous for hereditary hemochromatosis (HH)], i.e. the syndrome due to either HFE or non-HFE hemochromatosis gene mutations.
Family doctors and internal medicine specialists may diagnose and treat hemochromatosis. Other doctors also may be involved in diagnosing and treating the disease, including: Hematologists (blood disease specialists) Cardiologists (heart specialists)Can you have too much iron without having hemochromatosis? ›
Dysmetabolic Hyperferritinemia: All Iron Overload Is Not Hemochromatosis.Can you have high ferritin and not have hemochromatosis? ›
This may include inflammatory disorders, liver disease (particularly non-alcoholic steatohepatitis (NASH)/fatty liver), alcohol excess, malignancy, renal failure, and metabolic syndrome, which are each more common than hemochromatosis. Fatty liver is a very common cause of high ferritin in out-patients.Can you test negative for hemochromatosis and still have it? ›
If the genetic test is negative because mutations (C282Y and H63D) were not detected in the HFE gene, then there may be another reason for iron overload, such as another disease, or another form of hemochromatosis caused by a different gene. Further medical investigation will be required.How does hemochromatosis affect the brain? ›
The findings suggest that the gene mutation principally responsible for hereditary hemochromatosis may be a risk factor for developing movement disorders, such as Parkinson's disease, which is caused by a loss of nerve cells that produce the chemical messenger dopamine.Can stress cause hemochromatosis? ›
Secondary hemochromatosis is mostly due to intended or unintended iron exposure to the body or the iron overload due to stress-impaired iron metabolism, which has not been well-addressed [16,17].What should you not do if you have hemochromatosis? ›
- Avoid iron supplements and multivitamins containing iron. These can increase your iron levels even more.
- Avoid vitamin C supplements. Vitamin C increases absorption of iron. ...
- Avoid alcohol. ...
- Avoid eating raw fish and shellfish.
Hemochromatosis causes or exacerbates arthritis, diabetes, impotence, heart failure, cirrhosis of the liver and liver cancer. The liver is the organ most affected by hemochromatosis, because of its relatively large blood flow.What are the cognitive symptoms of hemochromatosis? ›
He reported instances suggestive of decreased attention, problems with new learning, memory failure and confusion.What is the most commonly affected organ by hemochromatosis? ›
This excess iron is stored in major organs, especially the liver. Over a period of years, the stored iron can cause severe damage that may lead to organ failure. It also can lead to long-lasting diseases, such as cirrhosis, diabetes and heart failure.
A liver biopsy offers a definitive diagnosis. Your doctor may recommend a biopsy if you have elevated iron levels in your blood, especially if your symptoms are consistent with hereditary hemochromatosis.How high does ferritin have to be to diagnose hemochromatosis? ›
Serum ferritin levels elevated higher than 200 mcg/L in premenopausal women and 300 mcg/L in men and postmenopausal women indicate primary iron overload due to hemochromatosis, especially when associated with high transferrin saturation and evidence of liver disease.What level of ferritin is considered hemochromatosis? ›
These are the two key tests to begin diagnosis. In hemochromatosis, ferritin levels are often above 200 mcg/L in women or 300 mcg/L in men, while transferrin saturation is typically higher than 40% in women or 50% in men.Do all siblings get hemochromatosis? ›
Because hereditary hemochromatosis is an autosomal recessive condition, children and especially siblings are at increased risk for the disease (4-6). Family screening for hereditary hemochromatosis is therefore recommended (7).Can you get Social Security disability for hemochromatosis? ›
The Social Security Administration does recognize haemochromatosis under Section 5.0 of the SSA's disability guidelines. However, a diagnosis of the condition itself will not automatically qualify you for Social Security Disability Insurance or Supplemental Security Income.What famous person has hemochromatosis? ›
Ernest Hemingway, one of America's greatest writers, died from hereditary hemochromatosis on July 2, 1961.
Many patients also have periodic limb movements in sleep (PLMS), and they may complain of insomnia and/or hypersomnia. Hereditary haemochromatosis is an autosomal recessive disease of iron metabolism in which increased intestinal absorption of iron leads to iron deposition in multiple organs.How does hemochromatosis affect life expectancy? ›
Most people with hemochromatosis have a normal life expectancy. Survival may be shortened in people who are not treated and develop cirrhosis or diabetes mellitus.What is the common cause of death in hemochromatosis? ›
Prognosis. Among affected persons, the iron concentration in the liver is a major determinant of the risk of cirrhosis (scarring) of the liver and, in turn, of hepatocellular carcinoma (liver cancer). These are the two major causes of death associated with hereditary hemochromatosis.What is the death rate of hemochromatosis? ›
Mortality is estimated to be 1.7 cases per 10,000 deaths.
People with genetic haemochromatosis are at greater risk of suffering with poor mental health than the general population. Key findings : In this study, we found 65% of respondents with genetic haemochromatosis experienced some level of anxiety and 79% experienced some level of depression.What end organ damage is hemochromatosis? ›
If left untreated, it can lead to progressive damage of the liver and lead to cirrhosis, hepatocellular carcinoma and other complications associated with iron overload in the tissues and organs.Is hemochromatosis classed as a critical illness? ›
Does critical illness cover payout for haemochromatosis? A critical illness cover policy is designed to protect you if you're diagnosed with a serious illness or permanent injury. It is well-known that haemochromatosis is not a severe medical condition so will not attract a payout from this type of cover.Is hemochromatosis a disability? ›
Hemochromatosis is listed in the Social Security Administration's (SSA) Blue Book (the impairment listing manual) as one of the conditions that may potentially qualify a claimant for Social Security Disability Insurance or Supplemental Security Income.Does hemochromatosis cause mental illness? ›
Neuropsychiatric symptoms, like fatigue and depressed mood, occur in iron overload , . However, specific psychiatric disorders during the course of hereditary hemochromatosis or secondary disorders of iron metabolism are rarely reported.