TFR2-Related Type 3 Hereditary Hemochromatosis and Arthralgia
TFR2-related type 3 hereditary hemochromatosis is a rare form of iron overload disorder characterized by mutations in the transferrin receptor 2 gene, with arthralgia (joint pain) being a prominent early symptom that typically affects the metacarpophalangeal joints and ankles, and does not respond to phlebotomy treatment. 1, 2
What is TFR2-Related Type 3 Hereditary Hemochromatosis?
TFR2-related hemochromatosis (also known as Type 3 HH) is one of the non-HFE forms of hereditary hemochromatosis. It is characterized by:
- Genetic mutations in the transferrin receptor 2 (TFR2) gene
- Abnormal iron metabolism leading to excessive iron deposition in organs
- Typically presents at a younger age than the more common HFE-related (Type 1) hemochromatosis
- Rare occurrence compared to HFE-related hemochromatosis
Pathophysiology
The underlying mechanism of TFR2-related hemochromatosis involves:
- Dysfunction of the transferrin receptor 2 protein, which plays a key role in iron sensing
- Decreased expression of hepcidin, the principal iron-regulatory hormone
- Abnormal regulation of the hepcidin-ferroportin axis
- Increased intestinal iron absorption and iron release from macrophages
- Progressive iron accumulation in parenchymal organs (liver, heart, pancreas, joints) 1, 3
Clinical Presentation and Symptoms
Patients with TFR2-related hemochromatosis typically present with:
- Arthralgia (joint pain) - often the earliest and most prominent symptom
- Elevated serum ferritin levels and transferrin saturation
- Low hepcidin/ferritin ratio
- Presentation typically in young adulthood (ages 25-41) 2
Other clinical manifestations may include:
- Abnormal liver function
- Liver fibrosis or cirrhosis
- Diabetes
- Hypogonadism
- Cardiomyopathy
- Skin pigmentation 4
What is Arthralgia in TFR2-Related Hemochromatosis?
Arthralgia refers to joint pain and is a common and significant symptom in hereditary hemochromatosis, particularly in TFR2-related type:
Characteristics of hemochromatosis-related arthralgia:
- Typically affects the 2nd and 3rd metacarpophalangeal joints (hands)
- Also commonly affects ankles (69.3%), hips (56.8%), and wrists (46.9%) 1
- Occurs at a younger age compared to typical osteoarthritis
- Features rapid progression to cartilage loss
- Characterized by exuberant osteophytes (bone spurs)
- Often includes chondrocalcinosis (calcium crystal deposits in joint cartilage) in about 50% of cases 1
Radiographic findings:
- Degenerative changes
- Joint space narrowing
- Osteophytes
- Subchondral cysts
- Chondrocalcinosis in approximately half of cases 1
Important clinical consideration:
Arthralgia in TFR2-related hemochromatosis does not typically respond to phlebotomy therapy and can develop or persist even while on maintenance therapy. This is a critical distinction from some other symptoms of iron overload that may improve with iron reduction. 1
Diagnosis
The diagnosis of TFR2-related hemochromatosis should be considered in:
- Young adults presenting with unexplained arthralgia
- Elevated transferrin saturation (TSAT) and ferritin levels
- Absence of HFE gene mutations (C282Y, H63D)
- Low hepcidin/ferritin ratio
- Liver iron content >100 μmol/g 2
Diagnostic workup includes:
- Serum iron studies (ferritin, transferrin saturation)
- Genetic testing for TFR2 mutations
- Assessment of liver iron content (MRI or biopsy)
- Evaluation for other organ involvement 1, 2
Treatment
Management of TFR2-related hemochromatosis includes:
- Phlebotomy (therapeutic blood removal) to reduce iron overload
- Monitoring of serum ferritin and transferrin saturation
- Screening for complications (liver disease, diabetes, cardiac involvement)
For arthralgia specifically:
- Analgesics and non-steroidal anti-inflammatory drugs
- Physiotherapy
- Joint replacement surgery in severe cases 1
Clinical Importance
Early diagnosis of TFR2-related hemochromatosis is crucial to:
- Prevent progressive liver damage and other organ complications
- Initiate appropriate treatment for arthralgia
- Screen family members for the condition
- Provide genetic counseling 2
Despite the rarity of TFR2-related hemochromatosis, awareness among physicians is important for early diagnosis and prevention of complications, particularly since arthralgia may be the earliest presenting symptom in young adults.