Hemochromatosis type 3

Alternate names

Hemochromatosis due to defect in transferrin receptor 2; HFE3; TFR2-related hereditary hemochromatosis

Definition

Hemochromatosis type 3 is a disease in which too much iron builds up in the body. This is also called iron overload.

Onset

Symptoms of hemochromatosis type 3 typically begin before 30-years-old.

Cause

• Hemochromatosis type 3 is caused by genetic changes (mutations or pathogenic variants) in the TFR2 gene.
• The TFR2 gene provides the body with instructions to make a protein that helps iron enter liver cells.
• Pathogenic variants in the TFR2 gene cause this protein to not be able to correctly tell the liver cells how much iron to absorb.
• This causes iron to accumulate in tissues and organs, which can result in organ damage.

Inheritance

Autosomal recessive inheritance, a 25% chance

The disease is inherited in an autosomal recessive manner. Which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene but do not show signs and symptoms of the condition.

Signs and symptoms

Accumulation of iron in the organs is toxic and can cause organ damage. While many organs can be affected, iron overload is especially likely to affect the liver, heart, and pancreas. Early symptoms of hemochromatosis type 3 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.

Diagnosis

A diagnosis of hemochromatosis type 3 is suspected when a doctor observes signs and symptoms of the disease. A doctor may decide to order laboratory tests including a liver biopsy, MRI, or blood test. The diagnosis can be confirmed with genetic testing.

Clinical features and symptoms of iron overload

• Weakness, chronic fatigue
• Abdominal pain
• Hepatomegaly
• Cirrhosis, hepatocellular carcinoma
• Diabetes mellitus
• Cardiomyopathy, ECG abnormalities (conduction disturbances)
• Hypogonadism (decreased libido and impotence in men, amenorrhea in women)
• Arthritis (especially if involving the metacarpophalangeal joint), arthralgia
• Progressive increase in skin pigmentation

Laboratory features

• Transferrin saturation >45% (normal range: 20%-35% saturation in males and females)
• Serum ferritin concentration usually >200 µg/L in females and >300 µg/L in males

Normal ranges:

• Children and adolescents: 15-150 µg/L
• Adult females: 20-200 µg/L
• Adult males: 20-300 µg/L
• Elevated liver enzymes and/or abnormal liver function tests
• Hyperglycemia

Liver biopsy. Findings on liver biopsy have been reported in some individuals with TFR2-HHC

• Histology; fibrosis or cirrhosis
• Elevated liver iron concentration (normal values: 10-35 µmol/g dry liver weight or 0.56-1.96 mg/g dry liver weight):

Imaging. Noninvasive techniques including MRI and SQUID developed to quantitate liver iron concentration have been applied to TFR2-HHC Hepcidin evaluation. Individuals with TFR2-HHC have decreased hepcidin concentrations in plasma and urine (similar to other types of autosomal recessive HHC). Hepcidin concentration in plasma and urine can be measured by mass-spectrometry-based assay and normalized for gender and age

Treatment

• Removal of excess iron by routine phlebotomy to maintain serum ferritin concentration at 50 ng/mL or lower and transferrin-iron saturation below 50%
• Lifelong hormone replacement therapy for hypogonadism
• Gonadotropins for fertility/pregnancy
• Nonsteroidal anti-inflammatory drugs and joint replacement for arthropathy
• Routine treatment for cardiac failure, diabetes mellitus, and hepatic complications.[1].

References

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NIH genetic and rare disease info

• NIH info on Hemochromatosis type 3

Hemochromatosis type 3 is a rare disease.

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