Medical Mystery of the Week

You have recieved your COVID19 immunizations and are practicing traditional medicine.

Your case is a 48-year-old man who was clinically well until 8 months ago when he developed fatigue and lethargy followed by an unintended weight loss of 9.1 kg. Three weeks before his visit he noted an increase in his abdominal girth and swelling of both  legs.
      His past medical history is pertinent for recently diagnosed type 2 diabetes mellitus (glycated hemoglobin of 6.1%) (treated with metformin), a normocytic anemia, and the occurrence of Mycoplasma pneumoniae pneumonia 16 months prior to his visit. He had consumed 24 beers weekly for 15 years.
      His review of systems is positive for constipation, decreased libido, intolerance to cold, and arthralgias of his ankles and knees.
     On your examination his temperature is 36.6°C, blood pressure  98/54 mm Hg, respirations 20 breaths/minute, and heart rate 64 beats/minute. His BMI is 27.3. Pertinent findings include jugular venous distension, a S3 gallop, ascites, and symmetrical 2+ edema of his lower legs extending up to his knees. He has mild palmar erythema but no spider angiomata. 
      Pertinent lab findings include a blood glucose of 402 mg/dL, a glycolated hemoglobin of 11.6%, a SGPT of 92 U/L, and an alkaline phosphatase of 172 U/L. His ascitic fluid is clear with 260 lymphocytes, 63 monocytes, 157 macrophages, an albumin of 1.0 g/dL, a total protein of 1.8 g/dL, and negative cytology for malignant cells. The results of abdominal (panels A, B, & C), cardiac (panels D & E), and abdominal/cardiac (panel F) MRIs are shown below.

  K, kidney; L, liver; LV, left ventricle; P, pancreas; RV, right ventricle; S, spleen.    
      What is your diagnosis, what test(s) would you order to confirm your suspicions, and what treatment, if any, do you recommend?
DIAGNOSIS: Hereditary hemochromatosis due to a mutated HFE gene, an upstream regulator of the master regulator of systemic iron homeostasis, hepcidin; this results in the unregulated expression of the iron exporter, ferroportin, with consequent increased iron absortion by duodenal enterocytes and increased exportation of iron from macrophages. Clinical manifestations typically occur in the fourth or fifth decade in men; onset is later in women, presumably due to  blood loss during menstruation.
      The presented case had iron deposits in his liver, heart, pancreas, joints, and pituitary gland with consequent development of micronodular cirrhosis, myocardopathy with CHF, type II diabetes mellitus, arthritis, and hypothyroidism. He had elevated levels of ferritin (3543 ug/L), iron (272 ug/dL), and transferrin saturation (96%). On biopsy, the liver was nodular with marked iron deposition in hepatocytes and bile ducts.
      The standard treatment for hereditary hemochromotosis is phlebotomy, which may take more than a year to normalize iron stores, and was, therefore, not practical in the presented case; he was treated with iron chealators (deferoxamine and deferiprone). Unfortuantely, he died of cardiac arrest one day after a 7 week hospitalization.

Cited reference: Moore, A.B., Wing, J.R., Goiffon, R.J., Leaf, R.K., Tsao, L., Misdraji, J. Case 25-2021: A 48-year-old man with fatigue and leg swelling. NEJM 385; 8: 745-754 (2021).