Clinicopathological Diagnosis and Treatment of Juvenile Hemochromatosis
Juvenile hemochromatosis (JH) is a rare and severe form of hereditary hemochromatosis (HH), an autosomal recessive disorder characterized by excessive intestinal absorption of iron, leading to iron overload in various organs. Unlike the more common type 1 HH, which is associated with mutations in the HFE gene and typically presents in adulthood, JH manifests earlier in life, usually in the first to third decades, and progresses more rapidly. This condition is associated with mutations in the hemojuvelin (HJV) gene, known as type 2A HH, or the human antimicrobial peptide (HAMP) gene, referred to as type 2B HH. JH is marked by acute and severe symptoms, including liver dysfunction, cardiomyopathy, diabetes, hypogonadism, and skin pigmentation. The primary therapeutic goal is iron depletion to normalize iron stores and prevent or mitigate organ damage.
Pathophysiology and Genetic Basis
The genetic basis of JH involves mutations in the HJV or HAMP genes, which play critical roles in iron metabolism. The HJV gene, located on chromosome 1q21, encodes hemojuvelin, a protein that regulates hepcidin expression. Hepcidin, encoded by the HAMP gene, is the central regulator of iron homeostasis, controlling iron absorption in the intestines and iron release from macrophages. Mutations in these genes lead to decreased hepcidin levels, resulting in unregulated iron absorption and subsequent iron overload.
In the case presented, a 31-year-old male patient was found to have two heterozygous mutations in the HJV gene: a premature termination mutation (962G>A and 963C>A; C321X) and a mutation in the signal peptide (18G>C; Q6H). These mutations were also identified in his father, while his mother carried a single heterozygous mutation (9G>C; E3D). These findings suggest that the C321X and Q6H mutations may be hotspots in Chinese patients with JH, contributing to the loss of hemojuvelin function and impaired iron metabolism.
Clinical Presentation and Laboratory Findings
The patient’s clinical presentation was consistent with JH, including polyuria, arterial hypertension, transaminasemia, increased skin pigmentation, and progressive sexual impotence. He was initially diagnosed with liver dysfunction and diabetes at age 23 and had been treated with insulin and liver protection therapy, but with limited success. Upon admission, laboratory tests revealed significant hyperglycemia (13.2 mmol/L), glycosuria, and biochemical evidence of liver damage, including elevated glutamyl transpeptidase (GGT) at 140 U/L, aspartate transaminase (AST) at 113 U/L, and alkaline phosphatase (ALP) at 162 U/L. His serum ferritin concentration was markedly elevated at 8729.2 ng/mL, with a transferrin saturation of 112.4%, indicative of severe iron overload.
Liver Biopsy and Histopathological Findings
A liver biopsy was performed to assess the extent of liver damage and iron deposition. Histopathological examination revealed ballooning degeneration of hepatocytes, portal lymphocytic infiltrates, and variable periportal inflammatory activity, consistent with interface hepatitis. Bridging necrosis was observed, along with fibrous septa and regenerative nodule formation, as demonstrated by reticulin staining. The Ishak scores for inflammation and fibrosis were 13 and 5, respectively, indicating significant liver damage.
Iron staining using Perls’ Prussian blue stain showed diffuse and extensive iron deposition in all hepatocytes, Kupffer cells, macrophages, biliary epithelial cells, and vascular endothelial cells. The iron distribution followed a decreasing gradient from periportal to centrolobular areas, a pattern typical of parenchymal iron overload. The Deugnier scores for parenchymal and mesenchymal iron deposition were 21 and 17, respectively, highlighting the severity of iron accumulation in the liver.
Diagnosis and Differential Diagnosis
The diagnosis of JH was confirmed based on the patient’s clinical presentation, laboratory findings, and genetic testing. Mutations in the HFE, HAMP, TFR2, SLC40A1, and HJV genes were analyzed, and only mutations in the HJV gene were identified. The presence of these mutations, combined with the clinical and histopathological findings, ruled out other forms of HH and confirmed the diagnosis of JH.
Treatment and Management
The primary treatment for JH is iron depletion, which can be achieved through phlebotomy or iron chelation therapy. In this case, the patient’s slightly lower hemoglobin level (121 g/L) precluded regular phlebotomy, so intravenous deferoxamine (2.5 g/d–3.5 g/d) was administered biweekly for approximately three years. Deferoxamine is an iron chelator that binds excess iron and facilitates its excretion. This treatment effectively reduced the patient’s serum ferritin to normal levels and improved his liver function, as evidenced by a near-normalization of AST levels. The skin hyperpigmentation completely disappeared after four months of treatment, although the elevated glucose levels and sexual impotence remained unchanged.
Prognosis and Long-Term Management
JH is associated with significant morbidity and mortality, primarily due to cardiac complications, which are the leading cause of death in untreated patients. The incidence of hypogonadism and cardiomyopathy in JH patients is high, at 94.6% and 43.2%, respectively. Liver involvement is a constant feature of HH, but cirrhosis at initial presentation is less common in JH, occurring in approximately 27% of cases. Hepatocellular carcinoma has not been reported in JH, likely because untreated individuals die prematurely from cardiac complications.
Long-term management of JH requires regular monitoring of iron parameters, liver function, cardiac function, and endocrine status. Iron chelation therapy or phlebotomy should be continued as needed to maintain normal iron stores. In some cases, combination therapy with both iron chelators and phlebotomy may be more effective than either treatment alone.
Conclusion
Juvenile hemochromatosis is a severe and rapidly progressive form of hereditary hemochromatosis that typically presents in the first to third decades of life. Early diagnosis and treatment are crucial to prevent irreversible organ damage and improve patient outcomes. Liver biopsy plays a vital role in accurately assessing the degree of iron deposition and fibrosis in JH patients. Mutations in the HJV gene, particularly the C321X and Q6H mutations, may be hotspots in Chinese patients with JH. Iron chelation therapy, such as deferoxamine, is an effective treatment option, especially in patients who cannot undergo regular phlebotomy. Continued research into the genetic and molecular mechanisms of JH will help improve diagnostic and therapeutic strategies for this rare but devastating condition.
doi.org/10.1097/CM9.0000000000000547
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