Aceruloplasminemia (ACP) is a rare, adult-onset, autosomal recessive disorder, characterized by systemic iron overload due to mutations in the Ceruloplasmin gene ( CP ), which in turn lead to absence or strong reduction of CP activity. CP is a ferroxidase that plays a key role in iron export from various cells, especially in the brain, where it maintains the appropriate iron homeostasis with neuroprotective effects. Brain iron accumulation makes ACP unique among systemic iron overload syndromes, e.g., various types of genetic hemochromatosis. The main clinical features of fully expressed ACP include diabetes, retinopathy, liver disease, and progressive neurological symptoms reflecting iron deposition in target organs. However, biochemical signs of the disease, namely a mild anemia mimicking iron deficiency anemia because of microcytosis and low transferrin saturation, but with “paradoxical” hyperferritinemia, usually precedes the onset of clinical symptoms of many years and sometimes decades. Prompt diagnosis and therapy are crucial to prevent neurological complications of the disease, as they are usually irreversible once established. In this mini-review we discuss some major issues about this rare disorder, pointing out the early clues to the right diagnosis, instrumental to reduce significant disability burden of affected patients.
Older people are at risk for cobalamin (vitamin B12) deficiency because of a number of common disorders (e.g. autoimmune gastritis) and drugs (e.g. antacids) that may alter its absorption and utilization. The prevalence of cobalamin deficiency increases with age, resulting particularly elevated in frail and institutionalized subjects. At variance with common sense, the diagnosis is far from simple and requires a high degree of suspicion, due to heterogeneity and non-specificity of the signs and symptoms, ranging from macrocytosis (with or without anemia) to neuropsychiatric manifestations, that characterize several other aging-related disorders, like hematological malignancies, diabetes, hypothyroidism or vasculopathies. Furthermore, the detection of low levels of serum vitamin B12 appears poorly sensitive and specific. Other biomarkers, like serum homocysteine or methylmalonic acid, have improved the diagnostic possibilities but are expensive, not widely available and may be influenced by some confounders (e.g. folate deficiency, or chronic renal failure). Early recognition and treatment are crucial, since a proportion of patients develop severe complications, such as bone marrow failure and irreversible neurological impairment. High-dose oral treatment has proven to be as effective as the parenteral route even in subjects with malabsorption, ensuring the complete resolution in the majority of cases. In this review, we trace the essential role of cobalamin in humans, the possible causes and impact of deficiency, the diagnostic challenges and the therapeutic options, between old and emerging concepts, with a particular focus on the elderly.
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