A 41-year-old Caucasian woman complaining of persistent diarrhea, diffuse neck myalgia, swollen fingers and fatigue was clinically evaluated.
Early morning fatigue and continuous neck pain started 6 months earlier and were initially attributed to stress by the patient's regular physician, who recommended psychotherapy. These symptoms did not improve and were worsened after a crisis of gastroenteritis due to seafood, associated with fever and severe abdominal pain, which resolved in 2 days. Despite improvement of the acute gastroenteritis, an intermittent diarrhea, without mucous or blood, persisted for another 2 months while the patient developed swollen fingers and a sudden outbreak of acne.
The patient's clinical history revealed that she had pre-eclampsia during her only pregnancy (9 years earlier), mumps and pancreatitis at 9 years old, and a myalgic crisis 4 years earlier, diagnosed at the time as fibromyalgia by her orthopedist. She had never smoked and was not under any medical treatment except for contraception with a levonorgestrel-releasing (20 mcg/day) intrauterine system for the previous 5 years with complete amenorrhea. The myalgic episode was resolved with cyclobenzaprine hydrochloride (15 mg/day) and a healthy sleep routine. Family history revealed that her father died of glioblastoma multiforme (GBM) and her grandfather died of abdominal cancer of unknown origin.
The only finding from the physical examination was a discrete tenderness upon palpation of the liver. Hematological values were within normal range. She presented with borderline high levels of LDL, HDL and total cholesterol (138 mg/dL, 48 mg/dL and 207 mg/dL). Triglyceride and VLDL cholesterol levels were 104 mg/dL and 21 mg/dL, respectively. The values for serum apolipoprotein A1 and B were 125 and 106 mg/dL, respectively. The patient tested negative for enteric parasites and fecal occult blood. Urinalysis revealed normal findings.
Except for a slightly elevated gamma-GT (88 U/L), all hepatic parameters were within normal limits. Thyroid ultrasonography revealed a colloid cyst in the right lobe, but the TSH, free T3 and T4 levels were normal. Although her fasting glucose was within normal limits, the patient presented with 2-hour post-challenge hyperglycemia (2 hPG > 140 mg/dL), which was suggestive of impaired glucose tolerance. The HbA1C value was 5.4%. The seric amylase level was 97 U/L and the lipase level was 42 U/L. The urea, creatinine, and electrolytes (Ca, inorganic P, Na, K and Mg) values were normal. Plasma ACTH was 9 pg/mL, serum HGH was 0.61 mg/L, cortisol levels were 8.5 and 7.7 mg/dL at 8 am and 4 pm, respectively, DHEA was 400 ng/dL and DHEA-s was 230 mug/dL.
Immunological investigation was positive for the following autoantibodies: ANAs (>=1/320:nuclear and metaphasic chromosome, >=1/160:cytoplasmic) and anti-smooth muscle. The panel was negative for p-ANCA, c-ANCA, CEA, Ca 19-9, ANA (nucleolar and nuclear mitotic apparatus), anti-nucleosome, anti-Sm, anti-RNP, anti-thyroglobulin, anti-thyroid peroxidase and native DNA. Serum levels of folic acid (327 ng/mL), vitamin B12 (438 ng/L), 25 hydroxyvitamin D (23 ng/mL) and 1, 25 dihydroxyvitamin D (42 pg/mL) were within normal ranges. The testosterone level was 34 ng/dL.
The echocardiogram was normal. Abdominal and pelvic ultrasonographies were normal except for a discrete increase in liver lipid infiltration. The intrauterine device was adequately positioned.
At this point, a dietary intervention (a low carbohydrate diet with lactose restriction) was prescribed, and the patient started a physical outdoor exercise program (50 minutes of walking, 5 times a week). Further immunologic testing was performed, but the results were either negative or normal (anti-mitochondrial antibody, Ro/SS-A antigen, La/SS-B antigen, serum immunoelectrophoresis, seric proteins electrophoresis, and serum IgA, IgG and IgM levels). During the following 5 months, the impaired glucose tolerance was controlled (2 hPG = 132 mg/dL), and she lost approximately 13 pounds (lb; starting weight: 156 lb, 5'8''); the diarrheic episodes diminished, but the fatigue persisted. The acne outbreaks were resolved with antibiotic therapy (tetracycline, 1 g/day, for 2 months). Family and colleagues ruled out personal and social problems. The physical exam was normal, and further laboratory tests were obtained.
Blood hematological parameters remained unremarkable, but at this time, serum ferritin was assessed. The elevated levels (216 mg/L) indicated that the patient most likely had an iron overload syndrome. She was screened for C282Y, H63D and S65C mutations and was homozygous positive for H63D. Abdominal magnetic resonance image (MRI) Iron Overload Syndrome, amenorrhea and IUS confirmed a hepatic iron overload of 50 mumol/g with a standard deviation of 30 mumol/g.
The patient was referred to a hepatologist who prescribed 4 therapeutic bleedings (phlebotomies) of 500 mL, once a month for 4 months. The intrauterine dispositive was removed to restart menstruation and allow for natural iron loss. Initially, the patient experienced extensive extremities edema, decreased immunological resistance and some dizziness after the phlebotomies. Diarrheic episodes ceased, and the fatigue decreased. Regular monthly menses were established after 2 months, and there was an increase in libido, although this was not a previous complaint. After all the phlebotomies, the serum ferritin levels returned to normal (52 mug/L) and the abdominal MRI findings showed a decrease in the hepatic iron concentration (40 mumol/g, standard deviation of 30 mumol/g).