Article Text
Summary
Rare diseases may be misdiagnosed if laboratory investigations show a common diagnosis instead. This is the story of 24-year-old male patient misdiagnosed as a case of hereditary spherocytosis at the age of 10 years. He received regular blood transfusions. Thorough investigations revealed microcytic anaemia, with results for all hereditary and acquired causes of haemolytic anemia negative, iron overload in the liver, stunted growth, insulin-dependent diabetes mellitis, hypercellular bone marrow and marked depletion of its iron stores. The transferrin level was very low when repeatedly measured, making congenital atransferrinaemia the most acceptable diagnosis for this case with haemochromatosis. Congenital atransferrinaemia is a very rare disease, with few cases recorded worldwide. Most cases died at a young age if not treated properly. Our patient is still alive although only recently diagnosed. He is now undergoing treatment with plasma transfusion, iron-chelating therapy and antituberculous treatment for pulmonary and osteoarthritic tuberculosis.
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BACKGROUND
Atransferrinaemia or hypotransferrinaemia is an unusual disease, with only 10 reported cases worldwide. It is one of the causes of haemochromatosis which, if not well treated with plasma transfusion and iron-chelating agents, may lead to death of the patient from congestive heart failure or chronic infections. Our patient has all the complications of haemochromatosis in the form of stunted growth, insulin-dependent diabetes mellitus (IDDM), hepatic iron deposition and a low transferrin level. The lowered immunity due to iron overload and diabetes mellitus resulted in pulmonary tuberculosis and tuberculous arthritis.
CASE PRESENTATION
The 24-year-old single, unemployed male patient was discovered to be diabetic and anaemic at the age of 10 years. At that time he was diagnosed by a general practitioner as a case of hereditary spherocytosis. He was splenectomised and kept on regular blood transfusions as his anaemia did not improve after surgery. The patient reported impairment of growth with failure to achieve puberty. Eight months previously the patient started to experience severe painful swelling of his right shoulder with limitation of movement. The condition was not preceded by trauma. He had proportionate stunted growth with signs of infantilism, body mass index (BMI) 23 kg/m2, skin hyperpigmentation, and a pansystolic murmur localised to the apex and a midsystolic murmur over the left sternal border. Examination of the respiratory system revealed increased tactile vocal fremitus (TVF), bronchial breathing, fine crepitations and increased vocal resonance over the right upper lobe, although he had no chest complaints. Abdominal examination revealed huge firm non-pulsating hepatomegaly. The right shoulder joint was swollen, red, hot and tender with limitation of all movements. Neurological examination was normal but he had symptoms of tingling sensations, and fundoscopic examination revealed bilateral non-proliferating diabetic retinopathy. Through the detailed investigation of this case with multisystem involvement we were able to reach a final diagnosis.
INVESTIGATIONS
Erythrocyte sedimentation rate (ESR): first hour, 129 mm; second hour 149 mm.
C-reactive protein (CRP): 12 IU/ml (normal: up to 6 IU/ml).
Microcytic hypochromic anaemia with anisopoikilocytosis.
Haemoglobin, 5.8 g/dl; mean corpuscular volume (MCV), 68 fl; reticulocyte count, 1.8×1010/l.
White blood cell count: 5.2×109/l with normal differential count.
Platelets: 5.4×1011/l, haemolytic profile: normal.
Total bilirubin: 1 mg/dl.
Aspartate aminotransferase (AST), 82 U/l (10–50); alanine aminotransferase (ALT), 73 U/l (10–50).
Alkaline phosphatase (ALP), 222 U/l ; γ-glutamyltransferase (GGT), 65 U/l.
Albumin: 3.9 g/dl.
International normalised ratio (INR), 1.2; glycated haemoglobin, 10%.
Creatinine: 0.4 mg/dl.
Hepatitis B surface antigen (HBs Ag), hepatitis B core antibody (HBc Ab) and hepatitis C virus (HCV) antibodies were negative
Iron: 26 μg/dl (37–158).
Total iron-binding capacity (TIBC): 28 μg/dl (230–480).
Transferrin saturation: 92.8%.
Ferritin: >2000 μg/l (28–379)
Follicle-stimulating hormone (FSH): 0.2 mIU/ml (1.5–13)
Luteinising hormone (LH): 0.2 mIU/ml (0.8–7.6)
Testosterone: 0.5 ng/ml (2.6–13.5)
Thyroid-stimulating hormone (TSH): 3.8 IU/ml (0.4–4)
Bone marrow aspirate
Hypercellular marrow with no evidence of dyserythropoiesis.
No ring sideroblasts. Iron stores of the bone marrow show marked depletion.
Transferrin: 35 mg/dl (n=200–360 mg/dl) repeated twice 1 week apart.
Ceruoloplasmin level: normal
Echocardiography
Left ventricular hypertrophy was more marked in the septal wall.
Small left ventricular cavity.
Systolic anterior motion abnormality of the mitral valve.
Mild aortic and mitral regurgitation.
Dilated aorta.
Ejection fraction: 65%
Chest x ray (fig 1)
Increased cardiothoracic ratio with left ventricular configuration..
Left apical ill-defined opacity with an adjacent apical pleural cap.
Patchy opacities in the right lung apex.
Chest x ray.
CT chest (fig 2)
Bilateral upper and mid zonal patchy opacities are seen mainly in a subpleural location.
No evidence of breaking down or calcification.
No hilar or mediastinal lymphadenopathy
CT chest.
CT-guided fine aspiration and core biopsy showed a granuloma formed of epithelioid cells with central breaking down and Langhan’s giant cells.
PCR was positive for Mycobacterium tuberculosis.
x Ray both hands
Generalised osteoporosis.
The bony age is approximately 16 years.
x Ray right shoulder
Disfigured proximal humeral configuration with subchondral humeral head cystic lesion.
Widened glenohumeral joint space.
Intact acromioclavicular articulation.
MRI of right shoulder joint
Diffuse thickening and enhancement of the right joint capsule involving its marrow recesses and reflections.
Mild free joint effusion.
Abdominal ultrasound
Marked hepatomegaly with diffuse pathology.
Main portal vein is dilated.
Surgically removed spleen.
Left testis is not seen either in the scrotum or in the inguinal canal.
Liver biopsy (fig 3) was positive for iron stain
Liver biopsy showing iron deposition.
DIFFERENTIAL DIAGNOSIS
Causes of haemochromatosis
Inherited causes
Hereditary haemochromatosis.
Neonatal haemochromatosis.
Juvenile haemochroatosis.
African haemochromatosis.
Thalassaemia major.
Hereditary sideroblastic anaemia.
Congenital dyserythropoietic anaemia.
Porphyria cutanea tarda.
Aceruoloplasminaemia
Congenital atransferrinaemia
Acquired causes
Repeated blood transfusion.
Chronic intake of medicinal iron.
Refractory anaemia with ringed sideroblasts.
TREATMENT
The patient’s ongoing treatment and follow-up comprise short-acting insulin 30 min before diet guided by postprandial blood sugar (PPBS), with a total dose ranging from 50 to 60 U/day, and long-acting insulin (Glargin) at bed time at a dose of 20 U.
Antituberculous treatment includes rifampicin 600 mg/day, isoniazide 300 mg/day, pyrazinamide 1000 mg/day and streptomycin 1000 mg every other day. The patient also received intravenous normal human plasma two units twice per week and a folic acid and vitamin B complex.
OUTCOME AND FOLLOW-UP
Follow-up after 1 month of treatment showed that fasting blood glucose was 185 mg%, and postprandial blood glucose was 260 mg%.
The total blood count showed a reticulocytic count of 9.83×1010/l and haemoglobin 9.8 g/dl, with nearly normal indices. Follow-up ESR showed 70 mm in the first hour and 90 mm in the second hour. Follow-up of liver enzymes and renal functions showed no further elevation.
DISCUSSION
This is a case of multiorgan system involvement: insulin-dependent diabetes mellitus, stunted growth, hypogonadism, hepatomegaly, evidence of cardiorespiratory involvement, right shoulder joint involvement and chronic severe microcytic hypochromic anaemia. Haemochromatosis is the key answer to all these findings in this patient. The combination of low serum iron and TIBC with very high ferritin is not seen in hereditary haemochromatosis which has high serum iron. The level of ceruloplasmin is normal in this patient. There are no skin manifestations of porphyria catenae tarda. Examination of the bone marrow showed no evidence of dyserythropoiesis or sideroblasts. Haemoglobin electrophoresis of the patient was normal. The investigations resulted in a diagnosis of atransferrinaemia.
Transferrin is a glycoprotein responsible for transferring iron from the intestine and reticuloendothelial system through the blood to cells forming haemoglobin, myoglobin and cytochromes, with a normal measured value of 200–400 mg/dl.1 In cases of atransferrinaemia, non-transferrin-bound iron (NTBI) is not used by erythroid cells but is taken up by hepatocytes and induces liver iron overload.2 A low level of transferrin can occur with chronic liver diseases due to decreased synthesis, with chronic inflammation or with renal and intestinal diseases due to increased loss, and with erythroleukaemia.3 In the few reported cases of atransferinaemia the level of transferrin measured ranged from trace to <39 mg/dl.4 In 2007 Aslan et al reported that there were 10 cases diagnosed in eight families, with only four having undergone molecular characterisation.5 The 10 cases were diagnosed during infancy, except one in the USA diagnosed at the age of 20 years.3 The level of transferrin is 35 mg/dl in our patient and unfortunately his parents are dead so we could not measure their transferrin level which has proved to be low in parents of children with congenital atransferrinaemia. There is no opportunity to conduct a molecular study of this case, and we are prepared to send samples abroad for molecular study.
LEARNING POINTS
Atransferrinaemia is a rare disease characterised by reduced delivery of iron to the bone marrow with reduced haemoglobin synthesis, and a secondary increase in iron absorption by the intestinal mucosa that results in severe iron overload. It is treated with plasma transfusion or concentrated purified transferrin with proper iron-chelating treatment to avoid complications of haemochromatosis.
Footnotes
Competing interests: none.
Patient consent: Patient/guardian consent was obtained for publication.