Fat-soluble vitamins, including vitamins A, D, E, and K, are energy-free molecules that are essential to the body’s functioning and life. Their intake is almost exclusively exogenous, i.e., dietary. As a result, fat-soluble vitamin deficiencies are rarer in industrialized countries than in countries with limited resources. Certain groups of people are particularly affected, such as newborns or growing children, pregnant or breastfeeding women, and elderly or isolated individuals. Deficiencies in vitamins A, D, E, and K are also relatively frequent in subjects with digestive tract disorders, liver diseases, chronic pathologies, or in intensive care patients. Deficiencies or excesses of fat-soluble vitamins are responsible for a variety of more or less specific clinical pictures. Certain syndromes are typical of fat-soluble vitamin deficiency, such as the combination of ophthalmological and immunity impairments in the case of vitamin A deficiency or hemorrhagic syndrome and osteopenia in the case of vitamin E deficiency. This is also the case for osteomalacia, muscular weakness, even falls, and rickets in the case of vitamin D deficiency. Diagnosis of a deficiency in one of the fat-soluble vitamins relies on blood tests, which are not always essential for routine use. In this context, a therapeutic test may be proposed. Treatment of deficiencies requires vitamin supplementation, a well-balanced diet, and treatment of the cause.

Food cobalamin malabsorption (FCM) represents a prevalent, often underdiagnosed, etiology of vitamin B12 deficiency, particularly within an aging population. Unlike pernicious anemia, an autoimmune disorder targeting intrinsic factor, FCM stems from the impaired release of cobalamin from food proteins, primarily due to age-related gastric changes, medication-induced gastric hypochlorhydria, metformin, or non-immune atrophic gastritis. The clinical presentation of FCM mirrors that of general cobalamin deficiency, encompassing a spectrum of neurological (peripheral neuropathy, cognitive decline), hematological (megaloblastic anemia), and gastrointestinal (glossitis, anorexia) manifestations. Given the potential for irreversible neurological sequelae, early detection and intervention are paramount. High-dose oral cobalamin (125–250 mcg daily) has demonstrated efficacy, offering a convenient and cost-effective alternative to parenteral administration.

Drug-induced agranulocytosis is a rare but life-threatening adverse reaction associated with numerous non-chemotherapy drugs. Management relies on immediate drug withdrawal, infection control, and, in selected patients, administration of granulocyte-colony stimulating factor (G-CSF). This review summarizes current knowledge on the determinants of epidemiology, clinical presentation, hematologic and biologic features, comorbidities, and outcomes influencing the decision to introduce G-CSF in drug-induced agranulocytosis. Evidence from observational studies and meta-analyses suggests that G-CSF shortens neutropenia duration and hospitalization, although its impact on mortality remains uncertain. The decision to use G-CSF should consider initial neutrophil count, presence of severe infection or sepsis, age, and comorbidities. Despite the accumulated experience, randomized controlled trials are still lacking, and treatment algorithms remain empirical.

Idiosyncratic drug-induced severe neutropenia and agranulocytosis are rare but potentially life-threatening adverse drug reactions. They cause profound neutrophil depletion after exposure to non-cytotoxic medications. Advances in supportive care have substantially reduced mortality. Long-term management nevertheless remains challenging. Clinicians must decide whether a structurally or pharmacologically related drug can be prescribed safely (cross-reactivity). They must also decide whether the culprit drug can ever be reintroduced (rechallenge). Current evidence supports an immune-mediated pathogenesis. It involves reactive drug metabolites, hapten formation, human leukocyte antigen (HLA)-restricted antigen presentation, and T-cell activation. The strength of evidence for cross-reactivity varies considerably across drug classes. Clinically meaningful cross-reactivity is well established for antithyroid thionamides. Evidence for beta-lactam antibiotics and thienopyridine antiplatelet agents remains limited, resting largely on case reports and pharmacovigilance data. For most other medications, evidence is insufficient to support generalized class-wide avoidance. Evidence supporting drug rechallenge is similarly heterogeneous. The most robust data concern clozapine. Carefully selected patients with previous neutropenia—but generally not agranulocytosis—may successfully undergo rechallenge under intensive hematologic monitoring, often with granulocyte colony-stimulating factor (G-CSF) support. Outside this setting, deliberate rechallenge is rarely justified. It should be reserved for exceptional clinical circumstances when no effective therapeutic alternative exists. This review summarizes current mechanistic insights. It evaluates the available evidence for cross-reactivity and rechallenge across major drug classes, discusses the emerging role of pharmacogenomics, and proposes a practical framework to guide individualized clinical decision-making. Permanent discontinuation of the culprit drug remains the standard approach. Advances in immunology, pharmacogenomics, and international pharmacovigilance registries are progressively enabling more personalized risk assessment.