A rare case of juvenile hemochromatosis with mixed causes of hyperferritinemia

Dear Editor,

A 36‐year‐old woman was admitted to our hospital because of exertional dyspnea for 1 month. She had been diagnosed for amenorrhea, diabetes, and hypothyroidism 1 year before admission. Laboratory tests showed increased N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) of 22 842 pg/mL (reference range: 0‐153 pg/mL), remarkably elevated serum ferritin of 3406 ng/mL (24‐336 ng/mL) and enhanced calculated transferrin saturation of 96.1% (20%‐50%). Echocardiography identified a dilated left ventricle with reduced ejection fraction of 36%. Magnetic resonance imaging (MRI) revealed severe iron deposition in the liver and mild deposition in the myocardium with T2* values of 1.0 msec and 17.6 msec (normal >20 msec), respectively (Figure 1A). Therefore, cardiomyopathy complicated with congestive heart failure was confirmed, secondary to iron overload. The diagnosis of juvenile hemochromatosis (JH) was genetically confirmed by identification of four compound heterozygous mutations in hemojuvelin (HJV or HFE2) gene: c.842T>C, c.963C>A, c.962G>A in exon 4, c.18G>C in exon 2 (Figure 1B). Unfortunately, the patient suddenly developed acute liver injury after 6‐day iron‐chelation therapy with deferasirox with a dose of 1200 mg/day. Despite the use of liver protectants and plasma exchange, she rapidly developed hypotension, renal insufficiency, refractory distributive shock and died a month later.

Figure 1.

A, Short‐axis plane of ventricle including the adjacent liver by T2‐weighted turbo‐spin echo sequence (the more the iron content, the lower the signal of the liver or myocardium, and the lower the value of T2 or T2*). B, Compound heterozygous mutations (c.842T>C, c.963C>A, c.962G>A and c.18G>C) in HJV gene (indicated by arrows). LV, left ventricle; RV, right ventricle

At the age of 21, the patient had been diagnosed with adult‐onset Still's disease (AOSD) because of sustaining fever, generalized body rash and multiple arthralgias for several months, when any other possible etiologies had been ruled out. A remarkably high level of ferritin >2000 ng/mL had lasted for years since the onset of AOSD, which had been regarded as one of criteria for the diagnosis. Her symptoms could partially resolve with empirical steroids and nonsteroidal anti‐inflammatory drugs but relapsed during dose reduction or withdrawal of the steroids. During the past decade, her fasting glucose and thyroid function had not been found abnormal until last hospitalization.

Hyperferritinemia occurs in a number of diseases, with or without iron overload.1 JH is a rare but most severe form of hereditary hemochromatosis (HH) with early onset and rapid progression. It is a rare autosomal‐recessive iron overload disorder caused by mutations in HJV or hepcidin (HAMP) gene. In addition to the classic triad of hepatic cirrhosis, diabetes, and skin pigmentation, JH is also characterized by cardiomyopathy, arthropathy, and hypogonadism before adolescence.2, 3 Mutations in HJV or HAMP gene involved in the synthesis of the iron regulatory peptide hormone hepcidin lead to decreased hepcidin levels and consequently to organic iron overload.1 Therefore, when hyperferritinemia is in company with high transferrin saturation (>50%) and organic (eg, hepatic, myocardial) iron overload detected by MRI or biopsy, genetic testing should be done to verify the diagnosis of HH.1, 3

AOSD is a rare multisystem autoinflammatory entity of uncertain etiology with cardinal features of unexplained hyperpyrexia, arthralgia, pleomorphic rash, and pharyngalgia.4 Although hyperferritinemia is present in 90% of the cases,1 there are no other signs of iron overload. Different sets of classification criteria were established for diagnosis in previous studies, among which the Yamaguchi's criteria had the highest sensitivity (78.57%) and specificity (87.14%) in Chinese population.5 This patient's initial constellation of symptoms met the Yamaguchi's criteria, whereas any other etiologies including JH could not address the full spectrum of the illness. Although arthralgia and hyperferritinemia are commonly observed in both conditions, hyperpyrexia (in 60%‐100% cases of AOSD) and skin rash (60%‐80%) as two most frequent clinical manifestations of AOSD have never been reported in JH.4 Therefore, it is highly suspected that AOSD might coexist with the genetic disorder of JH in this young woman, which to the best of our knowledge, should be the first case report.

In the coexistence of two rare disease entities as JH and AOSD, the overlapping symptoms and hyperferritinemia might have delayed the diagnosis and treatment of JH, which might have led to the irreversible outcome.

CONFLICT OF INTEREST

The authors declare no potential conflict of interest.