Abstract
Summary
Iron metabolism and markers hereof are altered in anorexia nervosa (AN) but far from completely understood. We report a case of extreme hyperferritinemia in a patient with AN and discuss the possible mechanisms and current knowledge about the association between hyperferritinemia and AN. A 20-year-old woman with a history of AN presented with bradycardia, weariness, and malaise in addition to an incidentally very high ferritin level. The symptoms disappeared spontaneously after a short admission. There were no signs suggestive of systemic, hematological, or malignant disease causing the very high concentration of ferritin. Her body weight was in decline, leading up to admission, but did initially increase after discharge accompanied by declining ferritin concentration. However, a clear association between ferritin dynamics and weight changes or physical activity was not identified and neither were other causes of the hyperferritinemia. Around one in four patients with AN have increased ferritin concentrations. Our case represents the highest ferritin concentration reported in a patient with AN without other underlying causes or comorbidities.
Learning points
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Perturbed iron metabolism is frequent in restrictive type anorexia nervosa but incompletely understood.
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Altered ferritin in anorexia nervosa may be linked to nutritional status.
Background
Anorexia nervosa (AN) has the highest mortality rate amongst psychiatric disorders (1, 2). The risk of mortality for patients with AN is up to two times higher compared with an age- and sex-matched population and more than five times higher if hospitalization is required (3). AN is a complex condition that is often treated by a multidisciplinary team consisting of physicians, dietitians, and mental health experts. It is well documented that medical stabilization and nutrition are important factors in the short-term outcome for patients with AN (4, 5, 6).
It is proposed that a greater comprehension of the physiological and biochemical deviations observed in patients with AN will result in a more appropriate, individualized, evidence-based therapy strategy for these patients (7, 8). Investigations into iron metabolism markers in AN are inconsistent, and a better understanding of iron metabolism in this condition is lacking. For example, ferritin has been found to be lower with AN and positively correlated to weight, supposedly related to oral intake (8). However, others have found increased ferritin levels with AN even in the absence of infection/inflammation. Thus, mild or severe stages are associated with temporary disturbed iron metabolism (9). There is some indication that this disturbance is corrected spontaneously during refeeding (9, 10, 11), though the physiological mechanisms for these findings remain unclear.
This report presents a case of extreme hyperferritinemia in a patient with AN and summarizes current knowledge about iron metabolism in AN.
Case presentation
A female in her early twenties who had recently experienced worsening of a 12-year-long history with AN was admitted with acute exhaustion, impaired ambulatory function, difficulty maintaining standing, and bradycardia. Over the course of 5 days leading up to admission, she also experienced headache and light-headedness with the sense of fever. She observed an increase in ankle and calf circumference bilaterally as well as periorbital edema. Aside from AN with primary amenorrhea and flares of obsessive compulsive disorder, she was deemed to be in good health. She had never used oral contraceptives. There was no history of drug, alcohol, or substance abuse or the use of prescription medications such as antacids or proton pump inhibitors that may interfere with iron metabolism. Over a 6-month period, her body weight (BW) went from 51.2 kg to 34.4 kg (–33%) on the day of admission, thus lowering her body mass index (BMI) to 13.8 kg/m2. Her very low-calorie diet consisted mainly of carbohydrates from vegetable sources and proteins of marine origin. Dietary fat was essentially avoided.
Her resting metabolism was calculated to be 1100 kcal. She exercised vigorously, going for walks and engaging in high-intensity interval training on a cycle ergometer. Based on reported physical activity prior to admission, we determined that her daily caloric expenditure was roughly 2060 kcal.
During hospitalization, she did not show any signs of infection, although a few slightly enlarged occipital lymph nodes and a nonspecific jugular, truncal, and palmar exanthema were found along with peripheral pitting edema. The exanthema was not highly red, and it yielded to pressure and did not present any signs of ulceration. The epidermis and body hair easily peeled off and lanugo hairs were widely apparent. There was no history of blood transfusion, increased iron intake, liver disease, or hematological disturbances and no family history of iron storage disorders. Cancer was not suspected because the patient had no constitutional symptoms, nor a prior medical history, to support this. Furthermore, there were no findings during the medical exam to support a suspicion of malignancy.
Investigation
Routine blood work on admission (Table 1) was abnormal for multiple indicators due to the deterioration of AN and continued weight loss. Of particular note was the extreme elevation of ferritin to 9096 µg/L. After spending 2 days in the hospital, both the symptoms and the degree of hyperferritinemia steadily subsided. The patient asked for a discharge at this point, challenging immediate and further investigation. Symptoms, overall health, and nutrition were prioritized above ferritin's etiology, since cancer or hemophagocytic lymphohistiocytosis was not suspected.
Laboratory results at admission, 3 and 6 months after discharge.
On admission |
After discharge | Reference values |
||
---|---|---|---|---|
At 3 months | At 6 months | |||
C-reactive protein, mg/L | 34.9 | 69 | <8.0 | |
Leucocytes, 109/L | 3.82 | – | 1.96 | 3.5–10.0 |
Neutrophilocytes, 109/L | 3.0 | 2.0–7.0 | ||
Potassium, mmol/L | 4.0 | 3.7 | 3.9 | 3.5–4,6 |
TSH, 10−3 IU/L | 5.4 | – | 9.9 | 0.3–4.5 |
Triiodothyronine, nmol/L | 0.65 | – | 0.6 | 1.1–2.5 |
Thyroxine (free), pmol/L | 8.8 | – | 11.7 | 12.0–22.0 |
ALT, U/L | 60 | 69 | 81 | 10–45 |
Alkaline phosphatase, U/L | 79 | 56 | 35–105 | |
LDH, U/L | 589 | – | 329 | 205–205 |
Albumin, g/L | 31 | 36 | 36 | 36–47 |
INR | 1.2 | 1.1 | 1.0 | <1.2 |
Hemoglobin, mmol/L | 7.4 | 6.9 | 6.8 | 7,3–9,5 |
EVF | 0.34 | 0.32 | 0.31 | 0.35–0.46 |
Urea, mmol/L | 7.9 | 13.6 | 8.9 | 2.6–6.4 |
Creatinine, µmol/L | 54 | 75 | 57 | 45–90 |
MCV, fL | 98 | 100 | 99 | 82–98 |
MCHC, mmol/L | 21.8 | 21.5 | 21.9 | 19.7–22.2 |
MCH, fmol | 2.14 | – | – | 1.7–2.1 |
Reticulocytes, 109/L | 46 | 45 | 63 | 31–97 |
Thrombocytes, 109/L | 101 | 176 | 156 | 165–400 |
Iron, µmol/L | 6 | 16 | 13 | 9–34 |
Transferrin, µmol/L | 25 | 25 | 23 | 24–41 |
Transferrin saturation | 0.11 | 0.12 | 0.28 | 0.1–0.5 |
Ferritin, µg/L | 9096 | 317 | 336 | 15–120 |
B12, pmol/L | 754 | 1049 | 1388 | 200–600 |
Folate, nmol/L | 47 | 30 | 46 | >6 |
Haptoglobin, g/L | – | 0.87 | – | 0.35–1.85 |
Coeruloplasmin, g/L | – | 0.31 | – | 0.15–0.45 |
IL-2 receptor, kU/L | – | 367 | – | 158–623 |
ALT, alanine aminotransaminase; EVF, erythrocyte volume fraction (hematocrit); IL, interleukin; INR, international normalized ratio; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; TSH, thyroid-stimulating hormone.
Outcome and follow-up
The patient was followed up with weekly weight and ferritin measurements. The latter continued to decline spontaneously without further signs of malignant disease or otherwise. A goal of weekly weight increments of 500-1000 g was agreed along with regular consults with a dietician. Her daily activity routine included walking and bouts of high-intensity training on a bike ergometer. Both a planned increase in calories and a suggestion to decrease daily exercise level were given.
With ferritin concentration decreasing spontaneously over the following 6 weeks from 9096 µg/L to a stable level of ≈300 µg/L, BW and BMI, albeit stable initially, also declined over the subsequent weeks to months (Fig. 1). During this period, she was admitted to the hospital because of asymptomatic bradycardia (lowest heart rate recorded of 32 beats per minute). She consistently reported feeling well and able to engage in physical activity, despite her inability to retain or gain weight after the first weight gain following her hospitalization. Most biochemical markers, including liver function tests, were unaltered over this period. Her mental well-being deteriorated somewhat in accordance with subsequent weight loss. One year after her initial hospitalization, she is now willing to enroll in a specialized treatment program, and her mental and physical health are expected to improve.
Ferritin and BMI in case patient during ≈6 months from admission. BMI, body mass index; CI, confidence interval.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-22-0405
Discussion
Elevated ferritin concentrations have previously been reported in AN (8, 9, 10, 11, 12, 13, 14, 15, 16). Although iron insufficiency from inadequate oral intake is common, iron metabolism is believed to be intact despite both high and low ferritin levels that can occur with AN (14). However, hyperferritinemia at the level we have presented has not been previously reported.
Elevated ferritin is a common finding both in general practice and in hospital. It may be indicative of underlying disease and has even been linked to premature death (17). Among causes for extreme hyperferritinemia in the high four- or even five-digit range are non-human immunodeficiency virus infections, solid tumors, hemophagocytic lymphohistiocytosis, liver failure, and hematological malignancies. Frequently, multiple underlying conditions are involved (18). History, clinical examination, and blood workup did not reveal a cause for the extreme hyperferritinemia in our case, and the ferritin level dropped spontaneously. The explanation was not investigated further during hospitalization due to the initial significant decline in ferritin without any signs of malignant disease, improved general well-being with symptom relief, and the patient's wish for discharge.
Previously, improvement of hyperferritinemia could not be associated with much certainty with changes in BW, nutritional stress, or physical activity (as assessed through interviews and reported to the dietician). Still, the partial and rapid improvement of the severe hyperferritinemia in conjunction with increases in BW and, at least temporarily, reported decreased physical activity, as well as improved nutritional status, suggests an association.
Iron metabolism and AN
Patients with AN often present with only mild to moderate hyperferritinemia and normal serum iron (9, 10, 12, 16). Among patients with eating disorders, it is primarily patients with restrictive AN who present with hyperferritinemia (8). Two studies have examined the prevalence of hyperferritinemia in patients with AN (12, 13). Both studies found that one in five with AN had ferritin > 200 µg/L. All subjects had C-reactive protein, erythrocyte sedimentation rate, and differential count, within reference ranges making increased ferritin due to infection or inflammation unlikely (13).
Ferritin concentration has been found to decrease progressively during refeeding (9). However, ferritin level at discharge was still higher with AN in comparison to the general population. Follow-up on the nutritional status 3 years after hospitalization and refeeding shows that the ferritin levels in patients with AN are below the reference values compared to the general population (11). No studies have shown a correlation between BMI or BW and ferritin concentration (10). Correspondingly, transferrin levels increase during refeeding pointing to transferrin as a potential biomarker of nutritional status (9). It may be that changes in iron-regulatory proteins and iron-responsive elements caused by catabolism above a certain threshold induced the overexpression of ferritin in spite of the patient being ferropenic (19). A study of the bone marrow changes in AN found that even though ferritin was increased in most patients, bone marrow samples revealed ferropenia in 3 out of 44 cases (20). This may indicate that despite normal reserves, AN patients do not mobilize iron in the bone marrow for hematogenesis. The suggestion of catabolism-driven changes in ferritin expression may be supported by higher ferritin levels found in AN compared with bulimia nervosa (21).
The iron metabolism and hematological status in patients with AN has seldom been investigated, and causes of increased ferritin concentration in people with AN are incompletely understood. Hepcidin affects iron absorption and metabolism and may play a pivotal role and positively correlates with ferritin in AN. In addition to ferritin, hepcidin decreased with nutritional rehabilitation but not to the levels of the age- and sex-matched control group hospitalized for acute problems other than malnutrition (14). Authors suggest that nutritional stress in hepatocytes due to malnutrition may be responsible for the increased ferritin and upregulated hepcidin. While we have no measurements of hepcidin in our case, it is likely that it may have been elevated due to the catabolic state, maybe through direct effects on hepatic hepcidin transcription and indirectly by increments in erythroferrone (myonectin), an erythroid regulator and hepcidin inhibitor, in skeletal muscle (22, 23). These combined effects may have been augmented by rigorous exercise which has been shown also to stimulate hepcidin, though not inducing hyperferritinemia in a trial of female long-distance runners (23).
Previous studies have suggested that one of the causes may be an inflammatory response due to the severe catabolism seen with the worsening of AN. However, usual inflammatory markers such as C-reactive protein or erythrocyte sedimentation rate have not been correlated to ferritin concentration and are usually not affected with AN per se either (12, 13, 14).
A previous case report on a patient with AN described a case of high serum ferritin (344 ng/mL), elevated liver enzymes, and signs of oxidative stress in the liver (16). The liver biopsy showed non-alcoholic steatohepatitis with signs of necroinflammatory changes, peroxidized liver products, and iron deposits in hepatocytes. Despite our patient’s severe hyperferritinemia, she had only slightly affected alanine aminotransferase of 60 U/L with normal bilirubin (18 µmol/L) and alkaline phosphatase (90 U/L). This indicates that our patient's hyperferritinemia was unrelated to liver failure. In addition, the absence of indications of hemolysis and lipidemia imply that interference with the ferritin assay (electrochemiluminescent immunoassay) is improbable but cannot be ruled out (24). In this regard, we did not test rheumatoid factor or other proteins.
Other possible hypotheses include decreased circulating blood volume associated with AN, causing destruction of red blood cells and thereby increasing iron release and increasing ferritin synthesis (12, 15). However, Papillard-Marechal et al. reported normal lactate dehydrogenase (LDH) and haptoglobin levels, suggesting that hemolysis was not the cause of hyperferritinemia (14). Regarding this, we did find elevated LDH, but no other indicators of hemolysis.
When patients with AN are admitted to the hospital, they often present with hypotension and bradycardia. Increased ferritin level may indicate reduced corrected left ventricular mass index (cLVM). A study tried to identify biochemical and non-burdensome predictors of reduced cLVM in a cohort of 284 women with AN and found that ferritin concentration and BMI were independent predictors of decreased cLVM (15). The authors hypothesise that associated muscle catabolism resulting in iron release from myoglobin leads to the observed rise in ferritin during starvation. However, an association of elevated myoglobin levels and concomitantly elevated ferritin levels has not been established.
In summary, we present a case of extreme hyperferritinemia in severe restrictive AN with ongoing weight loss following moderate-to-severe excess exercise. We ruled out several known causes for such extreme elevation of ferritin but did not identify any underlying causes.
This case highlights the knowledge gap in understanding iron metabolism in AN patients. To gain a better understanding of the metabolic allostasis in these patients, future studies should take iron metabolism into consideration.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work did not receive specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Patient consent
Written informed consent for publication of their clinical details was obtained from the patient.
Author contribution statement
All authors took part in all aspects of data procurement and analyses. All authors drafted, approved, and finalized the manuscript. HHT and CHA were the physicians responsible for the patient.
Acknowledgements
The authors thank coach and dietician Luise Sønder, Skive, Denmark, and the Medical Library, Viborg Regional Hospital.
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