Scurvy

Nutritional MONDO:0009412 Pathograph 23 Show in embeddings browser Vitamin Deficiency Disease

Scurvy is a nutritional deficiency disorder caused by prolonged dietary depletion of vitamin C (L-ascorbic acid), an essential reducing cofactor for Fe(II)/2-oxoglutarate-dependent dioxygenases and copper-dependent monooxygenases because humans lack functional L-gulonolactone oxidase. Deficient prolyl and lysyl hydroxylation destabilizes collagen triple helices and impairs extracellular matrix secretion in blood vessels, skin, gingiva, dentin, and bone, while impaired carnitine biosynthesis and dopamine beta-hydroxylase-mediated norepinephrine synthesis perturb cellular energy and catecholamine production, producing petechiae, perifollicular hemorrhage, ecchymoses, gingival bleeding and tooth loss, poor wound healing, bone pain, infantile pseudoparalysis, arthralgia, myalgia, fatigue, depression, and cognitive impairment that reverse with ascorbic acid replacement.

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Classifications

Harrison's Part
ENDOCRINOLOGY METABOLISM
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Pathophysiology

6
Defective Collagen Prolyl and Lysyl Hydroxylation
Depletion of L-ascorbic acid deprives endoplasmic reticulum prolyl and lysyl hydroxylases of the reducing cofactor required to convert proline to hydroxyproline and lysine to hydroxylysine, preventing stable collagen triple-helix folding, accelerating intracellular degradation, and decreasing mature procollagen secretion across dermal, gingival, and periarticular fibroblasts.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
collagen fibril organization GO:0030199 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased collagen fibril organization (GO:0030199). GO:0030199 is a biological process from the Gene Ontology.
procollagen-proline 4-dioxygenase activity GO:0004656 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased procollagen-proline 4-dioxygenase activity (GO:0004656). GO:0004656 is a molecular function from the Gene Ontology. procollagen-proline 3-dioxygenase activity GO:0019797 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased procollagen-proline 3-dioxygenase activity (GO:0019797). GO:0019797 is a molecular function from the Gene Ontology. procollagen-lysine 5-dioxygenase activity GO:0008475 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased procollagen-lysine 5-dioxygenase activity (GO:0008475). GO:0008475 is a molecular function from the Gene Ontology.
dermis UBERON:0002067 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dermis (UBERON:0002067). UBERON:0002067 is an anatomical location from the Uberon multi-species anatomy ontology. gingiva UBERON:0001828 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in gingiva (UBERON:0001828). UBERON:0001828 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Vascular Integrity Failure Underhydroxylated pericapillary and vascular-wall collagen weakens microvascular basement membranes and blood vessel walls.
Defective Osteoid Matrix Formation Impaired type I collagen maturation in osteoblasts prevents normal osteoid seam deposition and weakens bone matrix.
Defective Dentin and Periodontal Matrix Formation Impaired collagen hydroxylation in odontogenic and periodontal connective tissues disrupts dentin matrix production and tooth support.
Impaired Wound Healing Defective collagen synthesis and secretion impair granulation tissue remodeling and tensile wound repair.
Show evidence (2 references)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Vitamin C is essential in converting proline into 3- or 4- hydroxyproline and in converting lysine to hydroxylysine. This hydroxylation is needed to form stable triple-helix structures of collagen that will then be transported into the Golgi apparatus and ultimately secreted via secretory granules."
Details the biochemical requirement for vitamin C in prolyl and lysyl hydroxylation to stabilize triple-helical collagen for Golgi transport and secretion.
PMID:33236467 SUPPORT In vitro / ex vivo
"Vitamin C (ascorbic acid) is a cofactor of prolyl-hydroxylases that modify newly synthesized collagen on the route for secretion."
Experimentally confirms in human cells that ascorbic acid is required as a prolyl-hydroxylase cofactor for extracellular collagen secretion.
Vascular Integrity Failure
Loss of structurally intact collagen in capillary basement membranes and venular walls causes microvascular fragility and red blood cell extravasation into perifollicular dermis, subcutaneous tissues, gingiva, and synovial joints despite intact coagulation factor cascades.
capillary endothelial cell CL:0002144 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves capillary endothelial cell (CL:0002144). CL:0002144 is a cell type from the Cell Ontology. fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
collagen fibril organization GO:0030199 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased collagen fibril organization (GO:0030199). GO:0030199 is a biological process from the Gene Ontology.
blood vessel UBERON:0001981 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in blood vessel (UBERON:0001981). UBERON:0001981 is an anatomical location from the Uberon multi-species anatomy ontology. dermis UBERON:0002067 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dermis (UBERON:0002067). UBERON:0002067 is an anatomical location from the Uberon multi-species anatomy ontology. gingiva UBERON:0001828 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in gingiva (UBERON:0001828). UBERON:0001828 is an anatomical location from the Uberon multi-species anatomy ontology. skeletal joint UBERON:0000982 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skeletal joint (UBERON:0000982). UBERON:0000982 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Perifollicular Hemorrhages Fragile perifollicular capillaries rupture around hair follicles, producing petechial and perifollicular hemorrhage.
Ecchymoses Subcutaneous microvascular rupture causes confluent ecchymoses, especially over the lower extremities.
Gingival Bleeding Gingival microvascular fragility and periodontal collagen breakdown cause friable, bleeding gums.
Skin Discoloration Cutaneous red blood cell extravasation and hemosiderin deposition produce skin discoloration.
Petechiae Microvascular basement membrane and vessel wall damage cause pinpoint cutaneous hemorrhages (petechiae).
Arthralgias Synovial and periarticular microvascular hemorrhage (hemarthrosis) and connective tissue fragility produce painful joints.
Show evidence (2 references)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"vessel wall damage and bleeding that manifest through petechiae"
Confirms vessel wall damage resulting from collagen abnormality as the proximate cause of scorbutic microvascular bleeding.
PMID:37366866 SUPPORT Other
"Common manifestations include gingival bleeding, arthralgias, skin discoloration, impaired wound healing, perifollicular hemorrhage, and ecchymoses."
Summarizes the mucocutaneous and articular hemorrhagic manifestations of scorbutic vascular fragility.
Defective Osteoid Matrix Formation
Ascorbate-depleted osteoblasts fail to deposit a normal collagenous osteoid seam and exhibit altered bone transcriptional programs, causing cortical thinning, metaphyseal and subperiosteal bone pathology, bone pain, skeletal fragility with fractures, and periostitis-induced pseudoparalysis in infants.
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
ossification GO:0001503 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology.
bone tissue UBERON:0002481 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bone tissue (UBERON:0002481). UBERON:0002481 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Bone Pain Defective osteoid seam formation and subperiosteal/metaphyseal bone changes cause severe bone pain.
Increased Susceptibility to Fractures Impaired osteoblast osteoid matrix deposition reduces bone strength and increases fracture susceptibility.
Infantile Pseudoparalysis Scorbutic bone matrix failure and subperiosteal pathology produce painful periostitis in infants, leading to pseudoparalysis of affected limbs.
Show evidence (3 references)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"skin and bone abnormalities due to abnormal keratin production, inability of osteoblasts to produce the osteoid seam, and alterations in the transcriptional profile of the bone"
Demonstrates impaired osteoblast osteoid seam formation and altered bone transcriptional profile in scurvy.
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Skeletal findings among patients with low vitamin C levels include increased bone pain, skeletal fragility, and bone fractures"
Documents bone pain, skeletal fragility, and bone fractures in vitamin C deficiency.
PMID:29630239 SUPPORT INDIRECT Other
"Scurvy is a clinical syndrome resulting from vitamin C deficiency. Vitamin C is essential for the growth and repair of skin, cartilage, bone, and teeth."
States the normal physiological requirement for vitamin C in bone and cartilage growth and repair.
Defective Dentin and Periodontal Matrix Formation
Ascorbate depletion impairs odontoblast dentin matrix production and periodontal ligament collagen maintenance, weakening tooth anchorage and causing premature tooth loosening and loss.
odontoblast CL:0000060 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves odontoblast (CL:0000060). CL:0000060 is a cell type from the Cell Ontology. fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
dentinogenesis GO:0097187 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dentinogenesis (GO:0097187). GO:0097187 is a biological process from the Gene Ontology.
dentine UBERON:0001751 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in dentine (UBERON:0001751). UBERON:0001751 is an anatomical location from the Uberon multi-species anatomy ontology. periodontal ligament UBERON:0008266 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in periodontal ligament (UBERON:0008266). UBERON:0008266 is an anatomical location from the Uberon multi-species anatomy ontology. gingiva UBERON:0001828 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in gingiva (UBERON:0001828). UBERON:0001828 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Premature Loss of Teeth Modified dentin formation and periodontal collagen breakdown cause loosening and premature loss of teeth.
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"collagen abnormalities that manifest as loss of teeth due to modified dentine production"
Links scorbutic collagen and dentine matrix defects directly to tooth loss.
Impaired Carnitine Biosynthesis and Fatty Acid Transport
Ascorbate deficiency reduces the activity of Fe(II)/2-oxoglutarate-dependent hydroxylases (trimethyllysine and gamma-butyrobetaine dioxygenases) required for endogenous hepatic carnitine synthesis, impairing long-chain fatty acid transport into the skeletal muscle mitochondrial matrix and producing early fatigue, lassitude, and myalgia before overt hemorrhage appears.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
carnitine metabolic process GO:0009437 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased carnitine metabolic process (GO:0009437). GO:0009437 is a biological process from the Gene Ontology. long-chain fatty acid transport GO:0015909 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased long-chain fatty acid transport (GO:0015909). GO:0015909 is a biological process from the Gene Ontology.
gamma-butyrobetaine dioxygenase activity GO:0008336 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased gamma-butyrobetaine dioxygenase activity (GO:0008336). GO:0008336 is a molecular function from the Gene Ontology.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology. skeletal muscle tissue UBERON:0001134 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skeletal muscle tissue (UBERON:0001134). UBERON:0001134 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Fatigue Impaired carnitine-dependent mitochondrial beta-oxidation causes early low energy, weakness, and fatigue.
Myalgia Deficient skeletal muscle carnitine and mitochondrial fatty acid transport cause early muscle aches (myalgia).
Show evidence (2 references)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Lysine, methionine, and multiple hydroxylases are required for carnitine biosynthesis and fatty acid transport. In-vitro studies have revealed that the hydroxylases require a reductant, of which ascorbic acid is the most optimal [2]."
Establishes the requirement for ascorbic acid in the hydroxylases of carnitine biosynthesis and fatty acid transport.
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"low energy and muscle ache in the setting of not being able to transport long chain fatty acids into the mitochondrial matrix"
Connects impaired carnitine-dependent mitochondrial fatty-acid transport directly to early fatigue and muscle ache in vitamin C deficiency.
Impaired Dopamine Beta-Hydroxylase and Norepinephrine Synthesis
Ascorbate depletion deprives vesicular dopamine beta-hydroxylase of its reducing electron donor in noradrenergic neurons and adrenal chromaffin cells, impairing conversion of dopamine to norepinephrine alongside heightened neuronal oxidative vulnerability and contributing to depression and cognitive impairment in scurvy.
noradrenergic neuron CL:0008025 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves noradrenergic neuron (CL:0008025). CL:0008025 is a cell type from the Cell Ontology. chromaffin cell CL:0000166 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chromaffin cell (CL:0000166). CL:0000166 is a cell type from the Cell Ontology.
norepinephrine biosynthetic process GO:0042421 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased norepinephrine biosynthetic process (GO:0042421). GO:0042421 is a biological process from the Gene Ontology.
dopamine beta-monooxygenase activity GO:0004500 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased dopamine beta-monooxygenase activity (GO:0004500). GO:0004500 is a molecular function from the Gene Ontology.
central nervous system UBERON:0001017 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in central nervous system (UBERON:0001017). UBERON:0001017 is an anatomical location from the Uberon multi-species anatomy ontology. adrenal medulla UBERON:0001236 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in adrenal medulla (UBERON:0001236). UBERON:0001236 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Depression Impaired ascorbate-dependent neurotransmitter (norepinephrine) production and cortical oxidative stress are consistent with depressive symptoms in scurvy.
Cognitive Impairment Impaired ascorbate-dependent neurotransmitter synthesis and cortical neuronal oxidative stress are consistent with cognitive impairment in scurvy.
Show evidence (3 references)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Vitamin C acts as an electron donor for 15 mammalian enzymes. In the nervous system, it is essential to dopamine beta-hydroxylase activity."
Establishes vitamin C as an essential electron donor for nervous-system dopamine beta-hydroxylase activity.
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"secretory vesicles and adrenal chromaffin granules and is essential to norepinephrine synthesis."
Confirms that dopamine beta-hydroxylase in neurosecretory vesicles and adrenal chromaffin granules is required for norepinephrine synthesis.
DOI:10.1007/s40124-024-00315-9 SUPPORT INDIRECT Other
"symptoms including depression and cognitive impairment as well as pseudoparalysis"
Documents neuropsychiatric manifestations of scurvy including depression and cognitive impairment consistent with impaired ascorbate-dependent neurotransmitter synthesis.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Scurvy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Blood 4
Perifollicular Hemorrhages FREQUENT Petechiae HP:0000967 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is perifollicular hemorrhage, annotated with Petechiae (HP:0000967). HP:0000967 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37366866 SUPPORT Other
"Common manifestations include gingival bleeding, arthralgias, skin discoloration, impaired wound healing, perifollicular hemorrhage, and ecchymoses."
Perifollicular hemorrhage is explicitly listed as a common manifestation of scurvy.
Ecchymoses FREQUENT Bruising susceptibility HP:0000978 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is ecchymoses, annotated with Bruising susceptibility (HP:0000978). HP:0000978 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37366866 SUPPORT Other
"Common manifestations include gingival bleeding, arthralgias, skin discoloration, impaired wound healing, perifollicular hemorrhage, and ecchymoses."
Ecchymoses are explicitly listed as a common manifestation of scurvy.
PMID:37915623 SUPPORT Human clinical
"Here, we report on a 25-year-old male patient without any underlying conditions who presented with severe pain and ecchymoses of both lower extremities."
Case report documenting bilateral lower-extremity ecchymoses as a key presenting sign of scurvy.
Gingival Bleeding FREQUENT HP:0000225 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is gingival bleeding (HP:0000225). HP:0000225 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37366866 SUPPORT Other
"Common manifestations include gingival bleeding, arthralgias, skin discoloration, impaired wound healing, perifollicular hemorrhage, and ecchymoses."
Gingival bleeding is explicitly listed as a common manifestation of scurvy.
Petechiae HP:0000967 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is petechiae (HP:0000967). HP:0000967 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"vessel wall damage and bleeding that manifest through petechiae"
Identifies petechiae as a hemorrhagic manifestation of scorbutic vessel wall damage.
Head and Neck 1
Premature Loss of Teeth FREQUENT HP:0006480 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is loss of teeth, annotated with Premature loss of teeth (HP:0006480). HP:0006480 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"collagen abnormalities that manifest as loss of teeth due to modified dentine production"
Identifies loss of teeth as a common manifestation of scorbutic collagen and dentine abnormalities.
Integument 2
Skin Discoloration FREQUENT Abnormality of skin pigmentation HP:0001000 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin discoloration, annotated with Abnormality of skin pigmentation (HP:0001000). HP:0001000 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37366866 SUPPORT Other
"Common manifestations include gingival bleeding, arthralgias, skin discoloration, impaired wound healing, perifollicular hemorrhage, and ecchymoses."
Skin discoloration is listed among common clinical manifestations of scurvy.
Impaired Wound Healing FREQUENT Poor wound healing HP:0001058 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is impaired wound healing, annotated with Poor wound healing (HP:0001058). HP:0001058 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37366866 SUPPORT Other
"Common manifestations include gingival bleeding, arthralgias, skin discoloration, impaired wound healing, perifollicular hemorrhage, and ecchymoses."
Impaired wound healing is explicitly listed as a common manifestation of scurvy.
Musculoskeletal 2
Increased Susceptibility to Fractures HP:0002659 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is skeletal fragility and bone fractures, annotated with Increased susceptibility to fractures (HP:0002659). HP:0002659 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Skeletal findings among patients with low vitamin C levels include increased bone pain, skeletal fragility, and bone fractures"
Documents skeletal fragility and bone fractures in patients with low vitamin C levels.
Infantile Pseudoparalysis Functional motor deficit HP:0004302 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is infantile pseudoparalysis, annotated with Functional motor deficit (HP:0004302). HP:0004302 is a phenotype from the Human Phenotype Ontology.
HPO contains no dedicated term for pain-induced pseudoparalysis (verified via runoak -i sqlite:obo:hp search "pseudoparalysis" and "pseudo paralysis", both returning zero hits); bound to Functional motor deficit (HP:0004302) with periostitis-induced infantile immobility specified in preferred_term and description.
Show evidence (2 references)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"In infants, periostitis leads to pseudo paralysis."
Identifies periostitis-induced pseudoparalysis as a characteristic pediatric manifestation of scurvy.
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"symptoms including depression and cognitive impairment as well as pseudoparalysis"
Confirms pseudoparalysis among recognized clinical manifestations of scurvy.
Nervous System 2
Depression HP:0000716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is depression (HP:0000716). HP:0000716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"symptoms including depression and cognitive impairment"
Documents depression among psychological symptoms in individuals with scurvy.
Cognitive Impairment HP:0100543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"symptoms including depression and cognitive impairment"
Documents cognitive impairment among neuropsychiatric symptoms in individuals with scurvy.
Constitutional 4
Bone Pain HP:0002653 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is bone pain (HP:0002653). HP:0002653 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Skeletal findings among patients with low vitamin C levels include increased bone pain, skeletal fragility, and bone fractures"
Documents increased bone pain among skeletal findings in vitamin C deficiency.
Arthralgias FREQUENT HP:0002829 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is arthralgia (HP:0002829). HP:0002829 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37366866 SUPPORT Other
"Common manifestations include gingival bleeding, arthralgias, skin discoloration, impaired wound healing, perifollicular hemorrhage, and ecchymoses."
Arthralgias are explicitly listed as a common manifestation of scurvy.
Myalgia HP:0003326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is muscle ache, annotated with Myalgia (HP:0003326). HP:0003326 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"low energy and muscle ache in the setting of not being able to transport long chain fatty acids into the mitochondrial matrix"
Identifies muscle ache as an early clinical manifestation of vitamin C deficiency.
Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
No frequency band is assigned: the cited case report describes weakness/malaise/fatigue as "nonspecific constitutional symptoms", which supports the association but provides no quantitative cohort frequency data (per docs/frequency-evidence-guidelines.md, omission is preferred to inference).
Show evidence (1 reference)
PMID:37915623 SUPPORT Human clinical
"Scurvy, resulting from vitamin C deficiency, has nonspecific constitutional symptoms, including weakness, malaise, and fatigue."
Documents weakness, malaise, and fatigue as constitutional symptoms of scurvy.
💊

Medical Actions

1
Vitamin C Supplementation
Action: vitamin C supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is vitamin C supplementation, annotated with Nutritional Supplementation (NCIT:C15425). NCIT:C15425 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Supplementation NCIT:C15425
Agent: L-ascorbic acid CHEBI:29073 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses L-ascorbic acid (CHEBI:29073). CHEBI:29073 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Pharmacologic replacement with L-ascorbic acid (vitamin C) restores dioxygenase cofactor activity, rapidly resolving constitutional symptoms within days and reversing mucocutaneous hemorrhage and connective tissue defects over weeks.
Mechanism Target:
RESTORES Defective Collagen Prolyl and Lysyl Hydroxylation — Repletes the L-ascorbic acid cofactor required for prolyl and lysyl hydroxylase activity and mature collagen secretion.
Show evidence (2 references)
PMID:37366866 SUPPORT Other
"It can be adequately treated and prevented via vitamin C supplementation."
Supports vitamin C supplementation to reverse scorbutic connective tissue synthesis failure.
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Vitamin C is essential in converting proline into 3- or 4- hydroxyproline and in converting lysine to hydroxylysine."
Establishes the collagen prolyl and lysyl hydroxylation reactions restored by vitamin C repletion.
RESTORES Impaired Carnitine Biosynthesis and Fatty Acid Transport — Restores ascorbate-dependent hydroxylase activity in endogenous carnitine biosynthesis.
Show evidence (2 references)
PMID:37366866 SUPPORT Other
"It can be adequately treated and prevented via vitamin C supplementation."
Supports vitamin C supplementation to reverse biochemical defects of scurvy.
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Lysine, methionine, and multiple hydroxylases are required for carnitine biosynthesis and fatty acid transport. In-vitro studies have revealed that the hydroxylases require a reductant, of which ascorbic acid is the most optimal [2]."
Identifies the carnitine-biosynthetic hydroxylases whose optimal reductant is restored by ascorbic acid supplementation.
RESTORES Impaired Dopamine Beta-Hydroxylase and Norepinephrine Synthesis — Repletes the ascorbic acid electron donor required for dopamine beta-hydroxylase-mediated norepinephrine synthesis.
Show evidence (2 references)
PMID:37366866 SUPPORT Other
"It can be adequately treated and prevented via vitamin C supplementation."
Supports vitamin C supplementation to reverse clinical and biochemical manifestations of scurvy.
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Vitamin C acts as an electron donor for 15 mammalian enzymes. In the nervous system, it is essential to dopamine beta-hydroxylase activity."
Identifies nervous-system dopamine beta-hydroxylase activity as directly dependent on vitamin C electron donation.
Show evidence (1 reference)
PMID:37366866 SUPPORT Other
"It can be adequately treated and prevented via vitamin C supplementation."
Confirms that vitamin C supplementation is the definitive treatment and preventive measure for scurvy.
🌍

Environmental Factors

1
Vitamin C Deficiency
low vitamin C exposure ECTO:9000143 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is decreased low vitamin C exposure, annotated with exposure to vitamin C (ECTO:9000143). ECTO:9000143 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Inadequate dietary intake of vitamin C-containing fruits and vegetables due to severely restricted diets, food insecurity, alcoholism, or malabsorption, depleting body stores because humans cannot synthesize ascorbic acid endogenously.
Show evidence (2 references)
PMID:37915623 SUPPORT Human clinical
"He was diagnosed with scurvy due to a long history of staying indoors and inadequate intake of fruits or vegetables."
Demonstrates scurvy caused by prolonged inadequate dietary intake of fruits and vegetables.
PMID:37366866 SUPPORT Other
"In developed countries, it is mainly diagnosed in the elderly and malnourished individuals and is associated with alcoholism, low socio-economic status, and poor dietary habits."
Identifies contemporary nutritional and social risk factors for dietary vitamin C deficiency.
Mechanism Target:
TRIGGERS Defective Collagen Prolyl and Lysyl Hydroxylation — Dietary depletion of L-ascorbic acid removes the required cofactor for prolyl and lysyl hydroxylases.
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Vitamin C is essential in converting proline into 3- or 4- hydroxyproline and in converting lysine to hydroxylysine."
Demonstrates that vitamin C depletion removes the essential cofactor for collagen prolyl and lysyl hydroxylation.
TRIGGERS Impaired Carnitine Biosynthesis and Fatty Acid Transport — Dietary depletion of L-ascorbic acid impairs ascorbate-dependent hydroxylases in carnitine synthesis.
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Lysine, methionine, and multiple hydroxylases are required for carnitine biosynthesis and fatty acid transport. In-vitro studies have revealed that the hydroxylases require a reductant, of which ascorbic acid is the most optimal [2]."
Confirms that ascorbic acid depletion impairs the hydroxylases required for carnitine biosynthesis and fatty acid transport.
TRIGGERS Impaired Dopamine Beta-Hydroxylase and Norepinephrine Synthesis — Dietary depletion of L-ascorbic acid deprives dopamine beta-hydroxylase of its electron donor in norepinephrine synthesis.
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Vitamin C acts as an electron donor for 15 mammalian enzymes. In the nervous system, it is essential to dopamine beta-hydroxylase activity."
Links vitamin C deficiency directly to loss of essential cofactor support for dopamine beta-hydroxylase.
🔬

Biochemical Markers

1
Decreased Plasma and Leukocyte Ascorbic Acid (DECREASED)
Reference Ranges
23.0–114.0 umol/L
Scurvy-range severe deficiency (< 11.4 umol/L) Subclinical or borderline depletion (11.4–23.0 umol/L) Normal reference interval (23.0–114.0 umol/L)
Scurvy-range severe deficiency: Plasma vitamin C below 11.4 umol/L (0.2 mg/dL) corresponds to severe depletion at which clinical manifestations of scurvy occur.
Subclinical or borderline depletion: Plasma vitamin C below the 23 umol/L reference lower limit but at or above the 11.4 umol/L threshold associated with overt scurvy.
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"scurvy, a prolonged and severe form of vitamin C deficiency, are seen among those with plasma vitamin C concentrations below 0.2 mg/dL or 11.4 umol/L (reference range: 23–114 umol/L)."
Establishes the 11.4 umol/L (0.2 mg/dL) plasma threshold for clinical scurvy alongside the 23-114 umol/L reference interval.
Show evidence (2 references)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Vitamin C intake and storage can be measured through both plasma and leukocyte levels."
Confirms biochemical assessment of vitamin C status via plasma and leukocyte ascorbate measurements.
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"scurvy, a prolonged and severe form of vitamin C deficiency, are seen among those with plasma vitamin C concentrations below 0.2 mg/dL or 11.4 umol/L (reference range: 23–114 umol/L)."
Documents decreased plasma vitamin C concentrations (<11.4 umol/L) in patients manifesting clinical scurvy.
🔬

Diagnosis

2
Plasma and Leukocyte Vitamin C Assay (PRESENT)
Laboratory measurement of plasma and leukocyte ascorbic acid levels supports the clinical diagnosis of scurvy, with leukocyte levels reflecting tissue vitamin C stores more reliably than recent intake.
diagnostic blood testing NCIT:C217390 NCI Thesaurus (NCIT)
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"Vitamin C intake and storage can be measured through both plasma and leukocyte levels."
Establishes plasma and leukocyte vitamin C blood testing for evaluating ascorbate deficiency.
Skeletal Radiography for Scorbutic Bone Signs (PRESENT)
In pediatric and skeletal presentations, bone radiographs demonstrate characteristic scorbutic signs including the Frankel white line of provisional calcification, scorbutic rosary, and Pelkin metaphyseal spurs.
bone radiography NCIT:C137876 NCI Thesaurus (NCIT)
Show evidence (1 reference)
DOI:10.1007/s40124-024-00315-9 SUPPORT Other
"the Frankel sign (dense line at the end of metaphyses from increased width at the zone of provisional calcification)"
Describes characteristic metaphyseal radiographic signs used to recognize skeletal scurvy.
{ }

Source YAML

click to show 
name: Scurvy
creation_date: '2026-01-08T21:52:49Z'
description: >-
  Scurvy is a nutritional deficiency disorder caused by prolonged dietary
  depletion of vitamin C (L-ascorbic acid), an essential reducing cofactor for
  Fe(II)/2-oxoglutarate-dependent dioxygenases and copper-dependent
  monooxygenases because humans lack functional L-gulonolactone oxidase.
  Deficient prolyl and lysyl hydroxylation destabilizes collagen triple helices
  and impairs extracellular matrix secretion in blood vessels, skin, gingiva,
  dentin, and bone, while impaired carnitine biosynthesis and dopamine
  beta-hydroxylase-mediated norepinephrine synthesis perturb cellular energy and
  catecholamine production, producing petechiae, perifollicular hemorrhage,
  ecchymoses, gingival bleeding and tooth loss, poor wound healing, bone pain,
  infantile pseudoparalysis, arthralgia, myalgia, fatigue, depression, and
  cognitive impairment that reverse with ascorbic acid replacement.
category: Nutritional
parents:
- Vitamin Deficiency Disease
synonyms:
- ascorbic acid deficiency
- deficiency of vitamin C
- vitamin C deficiency
- scorbutus
disease_term:
  preferred_term: scurvy
  term:
    id: MONDO:0009412
    label: scurvy
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    evidence:
    - reference: PMID:37366866
      reference_title: "Scurvy: Rediscovering a Forgotten Disease."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Scurvy is a nutritional deficiency caused by low vitamin C levels that
        has been described since ancient times.
      explanation: >-
        Places scurvy among nutritional micronutrient deficiency disorders in
        metabolism and nutrition.
pathophysiology:
- name: Defective Collagen Prolyl and Lysyl Hydroxylation
  biological_scale: MOLECULAR
  description: >-
    Depletion of L-ascorbic acid deprives endoplasmic reticulum prolyl and lysyl
    hydroxylases of the reducing cofactor required to convert proline to
    hydroxyproline and lysine to hydroxylysine, preventing stable collagen
    triple-helix folding, accelerating intracellular degradation, and decreasing
    mature procollagen secretion across dermal, gingival, and periarticular
    fibroblasts.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  molecular_functions:
  - preferred_term: procollagen-proline 4-dioxygenase activity
    modifier: DECREASED
    term:
      id: GO:0004656
      label: procollagen-proline 4-dioxygenase activity
  - preferred_term: procollagen-proline 3-dioxygenase activity
    modifier: DECREASED
    term:
      id: GO:0019797
      label: procollagen-proline 3-dioxygenase activity
  - preferred_term: procollagen-lysine 5-dioxygenase activity
    modifier: DECREASED
    term:
      id: GO:0008475
      label: procollagen-lysine 5-dioxygenase activity
  biological_processes:
  - preferred_term: collagen fibril organization
    modifier: DECREASED
    term:
      id: GO:0030199
      label: collagen fibril organization
  locations:
  - preferred_term: dermis
    term:
      id: UBERON:0002067
      label: dermis
  - preferred_term: gingiva
    term:
      id: UBERON:0001828
      label: gingiva
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Vitamin C is essential in converting proline into 3- or 4- hydroxyproline
      and in converting lysine to hydroxylysine. This hydroxylation is needed to
      form stable triple-helix structures of collagen that will then be
      transported into the Golgi apparatus and ultimately secreted via secretory
      granules.
    explanation: >-
      Details the biochemical requirement for vitamin C in prolyl and lysyl
      hydroxylation to stabilize triple-helical collagen for Golgi transport and
      secretion.
  - reference: PMID:33236467
    reference_title: "Collagen release by human hepatic stellate cells requires vitamin C and is efficiently blocked by hydroxylase inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Vitamin C (ascorbic acid) is a cofactor of prolyl-hydroxylases that modify
      newly synthesized collagen on the route for secretion.
    explanation: >-
      Experimentally confirms in human cells that ascorbic acid is required as a
      prolyl-hydroxylase cofactor for extracellular collagen secretion.
  downstream:
  - target: Vascular Integrity Failure
    causal_link_type: DIRECT
    description: >-
      Underhydroxylated pericapillary and vascular-wall collagen weakens
      microvascular basement membranes and blood vessel walls.
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        vessel wall damage and bleeding that manifest through petechiae
      explanation: >-
        Connects vitamin C-deficient collagen synthesis defects to vessel wall
        damage and microvascular bleeding.
  - target: Defective Osteoid Matrix Formation
    causal_link_type: DIRECT
    description: >-
      Impaired type I collagen maturation in osteoblasts prevents normal osteoid
      seam deposition and weakens bone matrix.
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        skin and bone abnormalities due to abnormal keratin production,
        inability of osteoblasts to produce the osteoid seam, and alterations in
        the transcriptional profile of the bone
      explanation: >-
        Links vitamin C deficiency to osteoblast failure in osteoid matrix
        production.
  - target: Defective Dentin and Periodontal Matrix Formation
    causal_link_type: DIRECT
    description: >-
      Impaired collagen hydroxylation in odontogenic and periodontal connective
      tissues disrupts dentin matrix production and tooth support.
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        collagen abnormalities that manifest as loss of teeth due to modified
        dentine production
      explanation: >-
        Connects scorbutic collagen synthesis defects directly to modified
        dentine production.
  - target: Impaired Wound Healing
    causal_link_type: DIRECT
    description: >-
      Defective collagen synthesis and secretion impair granulation tissue
      remodeling and tensile wound repair.
    evidence:
    - reference: PMID:37366866
      reference_title: "Scurvy: Rediscovering a Forgotten Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It leads to a varied presentation, affecting multiple organ systems due
        to its role in the biochemical reactions of connective tissue synthesis.
        Common manifestations include gingival bleeding, arthralgias, skin
        discoloration, impaired wound healing, perifollicular hemorrhage, and
        ecchymoses.
      explanation: >-
        Links impaired connective tissue synthesis in scurvy directly to
        impaired wound healing.
- name: Vascular Integrity Failure
  biological_scale: TISSUE
  description: >-
    Loss of structurally intact collagen in capillary basement membranes and
    venular walls causes microvascular fragility and red blood cell
    extravasation into perifollicular dermis, subcutaneous tissues, gingiva, and
    synovial joints despite intact coagulation factor cascades.
  cell_types:
  - preferred_term: capillary endothelial cell
    term:
      id: CL:0002144
      label: capillary endothelial cell
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: collagen fibril organization
    modifier: DECREASED
    term:
      id: GO:0030199
      label: collagen fibril organization
  locations:
  - preferred_term: blood vessel
    term:
      id: UBERON:0001981
      label: blood vessel
  - preferred_term: dermis
    term:
      id: UBERON:0002067
      label: dermis
  - preferred_term: gingiva
    term:
      id: UBERON:0001828
      label: gingiva
  - preferred_term: skeletal joint
    term:
      id: UBERON:0000982
      label: skeletal joint
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      vessel wall damage and bleeding that manifest through petechiae
    explanation: >-
      Confirms vessel wall damage resulting from collagen abnormality as the
      proximate cause of scorbutic microvascular bleeding.
  - reference: PMID:37366866
    reference_title: "Scurvy: Rediscovering a Forgotten Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Common manifestations include gingival bleeding, arthralgias, skin
      discoloration, impaired wound healing, perifollicular hemorrhage, and
      ecchymoses.
    explanation: >-
      Summarizes the mucocutaneous and articular hemorrhagic manifestations of
      scorbutic vascular fragility.
  downstream:
  - target: Perifollicular Hemorrhages
    causal_link_type: DIRECT
    description: >-
      Fragile perifollicular capillaries rupture around hair follicles,
      producing petechial and perifollicular hemorrhage.
    evidence:
    - reference: PMID:37366866
      reference_title: "Scurvy: Rediscovering a Forgotten Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Common manifestations include gingival bleeding, arthralgias, skin
        discoloration, impaired wound healing, perifollicular hemorrhage, and
        ecchymoses.
      explanation: >-
        Confirms perifollicular hemorrhage as a hallmark hemorrhagic sign of
        scurvy.
  - target: Ecchymoses
    causal_link_type: DIRECT
    description: >-
      Subcutaneous microvascular rupture causes confluent ecchymoses, especially
      over the lower extremities.
    evidence:
    - reference: PMID:37366866
      reference_title: "Scurvy: Rediscovering a Forgotten Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Common manifestations include gingival bleeding, arthralgias, skin
        discoloration, impaired wound healing, perifollicular hemorrhage, and
        ecchymoses.
      explanation: >-
        Confirms ecchymoses as a common manifestation of scorbutic vascular
        fragility.
  - target: Gingival Bleeding
    causal_link_type: DIRECT
    description: >-
      Gingival microvascular fragility and periodontal collagen breakdown cause
      friable, bleeding gums.
    evidence:
    - reference: PMID:37366866
      reference_title: "Scurvy: Rediscovering a Forgotten Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Common manifestations include gingival bleeding, arthralgias, skin
        discoloration, impaired wound healing, perifollicular hemorrhage, and
        ecchymoses.
      explanation: >-
        Confirms gingival bleeding as a classic manifestation of scurvy.
  - target: Skin Discoloration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cutaneous red blood cell extravasation and hemosiderin deposition produce
      skin discoloration.
    evidence:
    - reference: PMID:37366866
      reference_title: "Scurvy: Rediscovering a Forgotten Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Common manifestations include gingival bleeding, arthralgias, skin
        discoloration, impaired wound healing, perifollicular hemorrhage, and
        ecchymoses.
      explanation: >-
        Lists skin discoloration alongside cutaneous hemorrhage in scurvy.
  - target: Petechiae
    causal_link_type: DIRECT
    description: >-
      Microvascular basement membrane and vessel wall damage cause pinpoint
      cutaneous hemorrhages (petechiae).
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        vessel wall damage and bleeding that manifest through petechiae
      explanation: >-
        Directly connects scorbutic vessel wall damage to petechiae.
  - target: Arthralgias
    causal_link_type: DIRECT
    description: >-
      Synovial and periarticular microvascular hemorrhage (hemarthrosis) and
      connective tissue fragility produce painful joints.
    evidence:
    - reference: PMID:37366866
      reference_title: "Scurvy: Rediscovering a Forgotten Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Common manifestations include gingival bleeding, arthralgias, skin
        discoloration, impaired wound healing, perifollicular hemorrhage, and
        ecchymoses.
      explanation: >-
        Confirms arthralgias among common clinical manifestations of scurvy.
- name: Defective Osteoid Matrix Formation
  biological_scale: CELLULAR
  description: >-
    Ascorbate-depleted osteoblasts fail to deposit a normal collagenous osteoid
    seam and exhibit altered bone transcriptional programs, causing cortical
    thinning, metaphyseal and subperiosteal bone pathology, bone pain, skeletal
    fragility with fractures, and periostitis-induced pseudoparalysis in
    infants.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: ossification
    modifier: DECREASED
    term:
      id: GO:0001503
      label: ossification
  locations:
  - preferred_term: bone tissue
    term:
      id: UBERON:0002481
      label: bone tissue
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      skin and bone abnormalities due to abnormal keratin production, inability
      of osteoblasts to produce the osteoid seam, and alterations in the
      transcriptional profile of the bone
    explanation: >-
      Demonstrates impaired osteoblast osteoid seam formation and altered bone
      transcriptional profile in scurvy.
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Skeletal findings among patients with low vitamin C levels include
      increased bone pain, skeletal fragility, and bone fractures
    explanation: >-
      Documents bone pain, skeletal fragility, and bone fractures in vitamin C
      deficiency.
  - reference: PMID:29630239
    reference_title: Vitamin C Deficiency.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Scurvy is a clinical syndrome resulting from vitamin C deficiency. Vitamin
      C is essential for the growth and repair of skin, cartilage, bone, and
      teeth.
    explanation: >-
      States the normal physiological requirement for vitamin C in bone and
      cartilage growth and repair.
  downstream:
  - target: Bone Pain
    causal_link_type: DIRECT
    description: >-
      Defective osteoid seam formation and subperiosteal/metaphyseal bone
      changes cause severe bone pain.
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Skeletal findings among patients with low vitamin C levels include
        increased bone pain, skeletal fragility, and bone fractures
      explanation: >-
        Directly links scorbutic skeletal pathology to increased bone pain.
  - target: Increased Susceptibility to Fractures
    causal_link_type: DIRECT
    description: >-
      Impaired osteoblast osteoid matrix deposition reduces bone strength and
      increases fracture susceptibility.
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Skeletal findings among patients with low vitamin C levels include
        increased bone pain, skeletal fragility, and bone fractures
      explanation: >-
        Directly links scorbutic bone matrix deficiency to skeletal fragility
        and fractures.
  - target: Infantile Pseudoparalysis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - periostitis
    description: >-
      Scorbutic bone matrix failure and subperiosteal pathology produce painful
      periostitis in infants, leading to pseudoparalysis of affected limbs.
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In infants, periostitis leads to pseudo paralysis.
      explanation: >-
        Establishes periostitis as the proximate skeletal intermediate causing
        pseudoparalysis in scorbutic infants.
- name: Defective Dentin and Periodontal Matrix Formation
  biological_scale: CELLULAR
  description: >-
    Ascorbate depletion impairs odontoblast dentin matrix production and
    periodontal ligament collagen maintenance, weakening tooth anchorage and
    causing premature tooth loosening and loss.
  cell_types:
  - preferred_term: odontoblast
    term:
      id: CL:0000060
      label: odontoblast
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: dentinogenesis
    modifier: DECREASED
    term:
      id: GO:0097187
      label: dentinogenesis
  locations:
  - preferred_term: dentine
    term:
      id: UBERON:0001751
      label: dentine
  - preferred_term: periodontal ligament
    term:
      id: UBERON:0008266
      label: periodontal ligament
  - preferred_term: gingiva
    term:
      id: UBERON:0001828
      label: gingiva
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      collagen abnormalities that manifest as loss of teeth due to modified
      dentine production
    explanation: >-
      Links scorbutic collagen and dentine matrix defects directly to tooth loss.
  downstream:
  - target: Premature Loss of Teeth
    causal_link_type: DIRECT
    description: >-
      Modified dentin formation and periodontal collagen breakdown cause
      loosening and premature loss of teeth.
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        collagen abnormalities that manifest as loss of teeth due to modified
        dentine production
      explanation: >-
        Directly connects defective dentine and collagen production to tooth
        loss in scurvy.
- name: Impaired Carnitine Biosynthesis and Fatty Acid Transport
  biological_scale: MOLECULAR
  description: >-
    Ascorbate deficiency reduces the activity of Fe(II)/2-oxoglutarate-dependent
    hydroxylases (trimethyllysine and gamma-butyrobetaine dioxygenases) required
    for endogenous hepatic carnitine synthesis, impairing long-chain fatty acid
    transport into the skeletal muscle mitochondrial matrix and producing early
    fatigue, lassitude, and myalgia before overt hemorrhage appears.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  molecular_functions:
  - preferred_term: gamma-butyrobetaine dioxygenase activity
    modifier: DECREASED
    term:
      id: GO:0008336
      label: gamma-butyrobetaine dioxygenase activity
  biological_processes:
  - preferred_term: carnitine metabolic process
    modifier: DECREASED
    term:
      id: GO:0009437
      label: carnitine metabolic process
  - preferred_term: long-chain fatty acid transport
    modifier: DECREASED
    term:
      id: GO:0015909
      label: long-chain fatty acid transport
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Lysine, methionine, and multiple hydroxylases are required for carnitine
      biosynthesis and fatty acid transport. In-vitro studies have revealed that
      the hydroxylases require a reductant, of which ascorbic acid is the most
      optimal [2].
    explanation: >-
      Establishes the requirement for ascorbic acid in the hydroxylases of
      carnitine biosynthesis and fatty acid transport.
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      low energy and muscle ache in the setting of not being able to transport
      long chain fatty acids into the mitochondrial matrix
    explanation: >-
      Connects impaired carnitine-dependent mitochondrial fatty-acid transport
      directly to early fatigue and muscle ache in vitamin C deficiency.
  downstream:
  - target: Fatigue
    causal_link_type: DIRECT
    description: >-
      Impaired carnitine-dependent mitochondrial beta-oxidation causes early
      low energy, weakness, and fatigue.
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        low energy and muscle ache in the setting of not being able to transport
        long chain fatty acids into the mitochondrial matrix
      explanation: >-
        Directly links impaired mitochondrial long-chain fatty acid transport to
        low energy in vitamin C deficiency.
  - target: Myalgia
    causal_link_type: DIRECT
    description: >-
      Deficient skeletal muscle carnitine and mitochondrial fatty acid transport
      cause early muscle aches (myalgia).
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        low energy and muscle ache in the setting of not being able to transport
        long chain fatty acids into the mitochondrial matrix
      explanation: >-
        Directly links impaired mitochondrial fatty-acid transport to muscle
        ache in vitamin C deficiency.
- name: Impaired Dopamine Beta-Hydroxylase and Norepinephrine Synthesis
  biological_scale: MOLECULAR
  description: >-
    Ascorbate depletion deprives vesicular dopamine beta-hydroxylase of its
    reducing electron donor in noradrenergic neurons and adrenal chromaffin
    cells, impairing conversion of dopamine to norepinephrine alongside
    heightened neuronal oxidative vulnerability and contributing to depression
    and cognitive impairment in scurvy.
  cell_types:
  - preferred_term: noradrenergic neuron
    term:
      id: CL:0008025
      label: noradrenergic neuron
  - preferred_term: chromaffin cell
    term:
      id: CL:0000166
      label: chromaffin cell
  molecular_functions:
  - preferred_term: dopamine beta-monooxygenase activity
    modifier: DECREASED
    term:
      id: GO:0004500
      label: dopamine beta-monooxygenase activity
  biological_processes:
  - preferred_term: norepinephrine biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0042421
      label: norepinephrine biosynthetic process
  locations:
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  - preferred_term: adrenal medulla
    term:
      id: UBERON:0001236
      label: adrenal medulla
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Vitamin C acts as an electron donor for 15 mammalian enzymes. In the
      nervous system, it is essential to dopamine beta-hydroxylase activity.
    explanation: >-
      Establishes vitamin C as an essential electron donor for nervous-system
      dopamine beta-hydroxylase activity.
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      secretory vesicles and adrenal chromaffin granules and is essential to
      norepinephrine synthesis.
    explanation: >-
      Confirms that dopamine beta-hydroxylase in neurosecretory vesicles and
      adrenal chromaffin granules is required for norepinephrine synthesis.
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      symptoms including depression and cognitive impairment as well as
      pseudoparalysis
    explanation: >-
      Documents neuropsychiatric manifestations of scurvy including depression
      and cognitive impairment consistent with impaired ascorbate-dependent
      neurotransmitter synthesis.
  downstream:
  - target: Depression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired ascorbate-dependent neurotransmitter (norepinephrine) production
      and cortical oxidative stress are consistent with depressive symptoms in
      scurvy.
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        symptoms including depression and cognitive impairment
      explanation: >-
        Documents depression among clinical symptoms of scurvy, consistent with
        impaired ascorbate-dependent neurotransmitter synthesis.
  - target: Cognitive Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired ascorbate-dependent neurotransmitter synthesis and cortical
      neuronal oxidative stress are consistent with cognitive impairment in
      scurvy.
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        symptoms including depression and cognitive impairment
      explanation: >-
        Documents cognitive impairment among clinical symptoms of scurvy,
        consistent with impaired ascorbate-dependent neurotransmitter
        synthesis.
phenotypes:
- category: Dermatological
  name: Perifollicular Hemorrhages
  frequency: FREQUENT
  description: >-
    Characteristic pinpoint hemorrhages surrounding hyperkeratotic hair
    follicles caused by pericapillary collagen fragility.
  phenotype_term:
    preferred_term: perifollicular hemorrhage
    term:
      id: HP:0000967
      label: Petechiae
  evidence:
  - reference: PMID:37366866
    reference_title: "Scurvy: Rediscovering a Forgotten Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Common manifestations include gingival bleeding, arthralgias, skin
      discoloration, impaired wound healing, perifollicular hemorrhage, and
      ecchymoses.
    explanation: >-
      Perifollicular hemorrhage is explicitly listed as a common manifestation
      of scurvy.
- category: Dermatological
  name: Ecchymoses
  frequency: FREQUENT
  description: >-
    Confluent subcutaneous hemorrhages and easy bruising, particularly over the
    lower extremities, resulting from capillary fragility.
  phenotype_term:
    preferred_term: ecchymoses
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:37366866
    reference_title: "Scurvy: Rediscovering a Forgotten Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Common manifestations include gingival bleeding, arthralgias, skin
      discoloration, impaired wound healing, perifollicular hemorrhage, and
      ecchymoses.
    explanation: >-
      Ecchymoses are explicitly listed as a common manifestation of scurvy.
  - reference: PMID:37915623
    reference_title: "Scurvy in a young man: a rare case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report on a 25-year-old male patient without any underlying
      conditions who presented with severe pain and ecchymoses of both lower
      extremities.
    explanation: >-
      Case report documenting bilateral lower-extremity ecchymoses as a key
      presenting sign of scurvy.
- category: Dermatological
  name: Skin Discoloration
  frequency: FREQUENT
  description: >-
    Abnormal cutaneous pigmentation and color change resulting from dermal
    hemorrhage, hemosiderin deposition, and impaired tissue repair.
  phenotype_term:
    preferred_term: Skin discoloration
    term:
      id: HP:0001000
      label: Abnormality of skin pigmentation
  evidence:
  - reference: PMID:37366866
    reference_title: "Scurvy: Rediscovering a Forgotten Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Common manifestations include gingival bleeding, arthralgias, skin
      discoloration, impaired wound healing, perifollicular hemorrhage, and
      ecchymoses.
    explanation: >-
      Skin discoloration is listed among common clinical manifestations of
      scurvy.
- category: Oral
  name: Gingival Bleeding
  frequency: FREQUENT
  description: >-
    Spontaneous gingival swelling, friability, and bleeding caused by defective
    mucosal and periodontal collagen.
  phenotype_term:
    preferred_term: gingival bleeding
    term:
      id: HP:0000225
      label: Gingival bleeding
  evidence:
  - reference: PMID:37366866
    reference_title: "Scurvy: Rediscovering a Forgotten Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Common manifestations include gingival bleeding, arthralgias, skin
      discoloration, impaired wound healing, perifollicular hemorrhage, and
      ecchymoses.
    explanation: >-
      Gingival bleeding is explicitly listed as a common manifestation of
      scurvy.
- category: Oral
  name: Premature Loss of Teeth
  frequency: FREQUENT
  description: >-
    Loosening and loss of teeth due to defective dentin production and
    periodontal ligament collagen breakdown.
  phenotype_term:
    preferred_term: loss of teeth
    term:
      id: HP:0006480
      label: Premature loss of teeth
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      collagen abnormalities that manifest as loss of teeth due to modified
      dentine production
    explanation: >-
      Identifies loss of teeth as a common manifestation of scorbutic collagen
      and dentine abnormalities.
- category: Dermatological
  name: Petechiae
  description: >-
    Pinpoint cutaneous and mucosal hemorrhages resulting from microvascular
    basement membrane and capillary wall fragility.
  phenotype_term:
    preferred_term: petechiae
    term:
      id: HP:0000967
      label: Petechiae
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      vessel wall damage and bleeding that manifest through petechiae
    explanation: >-
      Identifies petechiae as a hemorrhagic manifestation of scorbutic vessel
      wall damage.
- category: Musculoskeletal
  name: Bone Pain
  description: >-
    Deep extremity and metaphyseal bone pain caused by defective osteoid seam
    deposition and subperiosteal hemorrhage.
  phenotype_term:
    preferred_term: bone pain
    term:
      id: HP:0002653
      label: Bone pain
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Skeletal findings among patients with low vitamin C levels include
      increased bone pain, skeletal fragility, and bone fractures
    explanation: >-
      Documents increased bone pain among skeletal findings in vitamin C
      deficiency.
- category: Musculoskeletal
  name: Increased Susceptibility to Fractures
  description: >-
    Skeletal fragility and pathologic or low-trauma bone fractures caused by
    impaired osteoblast osteoid production and cortical thinning.
  phenotype_term:
    preferred_term: skeletal fragility and bone fractures
    term:
      id: HP:0002659
      label: Increased susceptibility to fractures
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Skeletal findings among patients with low vitamin C levels include
      increased bone pain, skeletal fragility, and bone fractures
    explanation: >-
      Documents skeletal fragility and bone fractures in patients with low
      vitamin C levels.
- category: Musculoskeletal
  name: Infantile Pseudoparalysis
  description: >-
    Apparent limb paralysis and voluntary immobility in scorbutic infants
    secondary to severe pain from long-bone periostitis and subperiosteal
    hemorrhage rather than primary neuromuscular denervation.
  notes: >-
    HPO contains no dedicated term for pain-induced pseudoparalysis (verified
    via runoak -i sqlite:obo:hp search "pseudoparalysis" and "pseudo
    paralysis", both returning zero hits); bound to Functional motor deficit
    (HP:0004302) with periostitis-induced infantile immobility specified in
    preferred_term and description.
  phenotype_term:
    preferred_term: infantile pseudoparalysis
    term:
      id: HP:0004302
      label: Functional motor deficit
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In infants, periostitis leads to pseudo paralysis.
    explanation: >-
      Identifies periostitis-induced pseudoparalysis as a characteristic
      pediatric manifestation of scurvy.
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      symptoms including depression and cognitive impairment as well as
      pseudoparalysis
    explanation: >-
      Confirms pseudoparalysis among recognized clinical manifestations of
      scurvy.
- category: Musculoskeletal
  name: Arthralgias
  frequency: FREQUENT
  description: >-
    Joint pain resulting from hemarthrosis, periarticular hemorrhage, and
    connective tissue fragility.
  phenotype_term:
    preferred_term: arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:37366866
    reference_title: "Scurvy: Rediscovering a Forgotten Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Common manifestations include gingival bleeding, arthralgias, skin
      discoloration, impaired wound healing, perifollicular hemorrhage, and
      ecchymoses.
    explanation: >-
      Arthralgias are explicitly listed as a common manifestation of scurvy.
- category: Musculoskeletal
  name: Myalgia
  description: >-
    Early diffuse muscle aches linked to impaired carnitine biosynthesis and
    mitochondrial fatty-acid transport as well as intramuscular microhemorrhage.
  phenotype_term:
    preferred_term: muscle ache
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      low energy and muscle ache in the setting of not being able to transport
      long chain fatty acids into the mitochondrial matrix
    explanation: >-
      Identifies muscle ache as an early clinical manifestation of vitamin C
      deficiency.
- category: Psychiatric
  name: Depression
  description: >-
    Depressed mood and affective disturbance associated with impaired
    ascorbate-dependent neurotransmitter synthesis in scurvy.
  phenotype_term:
    preferred_term: depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      symptoms including depression and cognitive impairment
    explanation: >-
      Documents depression among psychological symptoms in individuals with
      scurvy.
- category: Neurologic
  name: Cognitive Impairment
  description: >-
    Reversible cognitive dysfunction associated with severe vitamin C depletion,
    impaired neurotransmitter production, and neuronal oxidative stress.
  phenotype_term:
    preferred_term: cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      symptoms including depression and cognitive impairment
    explanation: >-
      Documents cognitive impairment among neuropsychiatric symptoms in
      individuals with scurvy.
- category: Constitutional
  name: Fatigue
  description: >-
    Early constitutional weakness, malaise, and low energy related to impaired
    carnitine-dependent fatty-acid oxidation and catecholamine synthesis.
  notes: >-
    No frequency band is assigned: the cited case report describes
    weakness/malaise/fatigue as "nonspecific constitutional symptoms", which
    supports the association but provides no quantitative cohort frequency data
    (per docs/frequency-evidence-guidelines.md, omission is preferred to
    inference).
  phenotype_term:
    preferred_term: fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:37915623
    reference_title: "Scurvy in a young man: a rare case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Scurvy, resulting from vitamin C deficiency, has nonspecific
      constitutional symptoms, including weakness, malaise, and fatigue.
    explanation: >-
      Documents weakness, malaise, and fatigue as constitutional symptoms of
      scurvy.
- category: Dermatological
  name: Impaired Wound Healing
  frequency: FREQUENT
  description: >-
    Delayed wound closure and scar dehiscence caused by defective collagen
    hydroxylation and fibril assembly.
  phenotype_term:
    preferred_term: impaired wound healing
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: PMID:37366866
    reference_title: "Scurvy: Rediscovering a Forgotten Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Common manifestations include gingival bleeding, arthralgias, skin
      discoloration, impaired wound healing, perifollicular hemorrhage, and
      ecchymoses.
    explanation: >-
      Impaired wound healing is explicitly listed as a common manifestation of
      scurvy.
biochemical:
- name: Decreased Plasma and Leukocyte Ascorbic Acid
  presence: DECREASED
  notes: >-
    Overt clinical scurvy typically occurs when plasma vitamin C concentrations
    fall below 11.4 umol/L (0.2 mg/dL; reference range 23-114 umol/L);
    leukocyte ascorbate better reflects tissue stores than recent dietary
    intake.
  reference_ranges:
  - lower_bound: 23.0
    upper_bound: 114.0
    unit: umol/L
    interpretation_bands:
    - name: Scurvy-range severe deficiency
      upper_bound: 11.4
      unit: umol/L
      abnormal_flag: LOW
      interpretation: >-
        Plasma vitamin C below 11.4 umol/L (0.2 mg/dL) corresponds to severe
        depletion at which clinical manifestations of scurvy occur.
    - name: Subclinical or borderline depletion
      lower_bound: 11.4
      upper_bound: 23.0
      unit: umol/L
      abnormal_flag: LOW
      interpretation: >-
        Plasma vitamin C below the 23 umol/L reference lower limit but at or
        above the 11.4 umol/L threshold associated with overt scurvy.
    - name: Normal reference interval
      lower_bound: 23.0
      upper_bound: 114.0
      unit: umol/L
      abnormal_flag: NORMAL
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        scurvy, a prolonged and severe form of vitamin C deficiency, are seen
        among those with plasma vitamin C concentrations below 0.2 mg/dL or
        11.4 umol/L (reference range: 23–114 umol/L).
      explanation: >-
        Establishes the 11.4 umol/L (0.2 mg/dL) plasma threshold for clinical
        scurvy alongside the 23-114 umol/L reference interval.
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Vitamin C intake and storage can be measured through both plasma and
      leukocyte levels.
    explanation: >-
      Confirms biochemical assessment of vitamin C status via plasma and
      leukocyte ascorbate measurements.
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      scurvy, a prolonged and severe form of vitamin C deficiency, are seen
      among those with plasma vitamin C concentrations below 0.2 mg/dL or 11.4
      umol/L (reference range: 23–114 umol/L).
    explanation: >-
      Documents decreased plasma vitamin C concentrations (<11.4 umol/L) in
      patients manifesting clinical scurvy.
environmental:
- name: Vitamin C Deficiency
  exposure_term:
    preferred_term: low vitamin C exposure
    modifier: DECREASED
    term:
      id: ECTO:9000143
      label: exposure to vitamin C
  description: >-
    Inadequate dietary intake of vitamin C-containing fruits and vegetables due
    to severely restricted diets, food insecurity, alcoholism, or malabsorption,
    depleting body stores because humans cannot synthesize ascorbic acid
    endogenously.
  influences_mechanisms:
  - target: Defective Collagen Prolyl and Lysyl Hydroxylation
    environmental_effect: TRIGGERS
    description: >-
      Dietary depletion of L-ascorbic acid removes the required cofactor for
      prolyl and lysyl hydroxylases.
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Vitamin C is essential in converting proline into 3- or
        4- hydroxyproline and in converting lysine to hydroxylysine.
      explanation: >-
        Demonstrates that vitamin C depletion removes the essential cofactor
        for collagen prolyl and lysyl hydroxylation.
  - target: Impaired Carnitine Biosynthesis and Fatty Acid Transport
    environmental_effect: TRIGGERS
    description: >-
      Dietary depletion of L-ascorbic acid impairs ascorbate-dependent
      hydroxylases in carnitine synthesis.
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Lysine, methionine, and multiple hydroxylases are required for carnitine
        biosynthesis and fatty acid transport. In-vitro studies have revealed
        that the hydroxylases require a reductant, of which ascorbic acid is the
        most optimal [2].
      explanation: >-
        Confirms that ascorbic acid depletion impairs the hydroxylases required
        for carnitine biosynthesis and fatty acid transport.
  - target: Impaired Dopamine Beta-Hydroxylase and Norepinephrine Synthesis
    environmental_effect: TRIGGERS
    description: >-
      Dietary depletion of L-ascorbic acid deprives dopamine beta-hydroxylase of
      its electron donor in norepinephrine synthesis.
    evidence:
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Vitamin C acts as an electron donor for 15 mammalian enzymes. In the
        nervous system, it is essential to dopamine beta-hydroxylase activity.
      explanation: >-
        Links vitamin C deficiency directly to loss of essential cofactor
        support for dopamine beta-hydroxylase.
  evidence:
  - reference: PMID:37915623
    reference_title: "Scurvy in a young man: a rare case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was diagnosed with scurvy due to a long history of staying indoors and
      inadequate intake of fruits or vegetables.
    explanation: >-
      Demonstrates scurvy caused by prolonged inadequate dietary intake of
      fruits and vegetables.
  - reference: PMID:37366866
    reference_title: "Scurvy: Rediscovering a Forgotten Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In developed countries, it is mainly diagnosed in the elderly and
      malnourished individuals and is associated with alcoholism, low
      socio-economic status, and poor dietary habits.
    explanation: >-
      Identifies contemporary nutritional and social risk factors for dietary
      vitamin C deficiency.
diagnosis:
- name: Plasma and Leukocyte Vitamin C Assay
  presence: PRESENT
  description: >-
    Laboratory measurement of plasma and leukocyte ascorbic acid levels supports
    the clinical diagnosis of scurvy, with leukocyte levels reflecting tissue
    vitamin C stores more reliably than recent intake.
  diagnosis_term:
    preferred_term: diagnostic blood testing
    term:
      id: NCIT:C217390
      label: Diagnostic Blood Testing
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Vitamin C intake and storage can be measured through both plasma and
      leukocyte levels.
    explanation: >-
      Establishes plasma and leukocyte vitamin C blood testing for evaluating
      ascorbate deficiency.
- name: Skeletal Radiography for Scorbutic Bone Signs
  presence: PRESENT
  description: >-
    In pediatric and skeletal presentations, bone radiographs demonstrate
    characteristic scorbutic signs including the Frankel white line of
    provisional calcification, scorbutic rosary, and Pelkin metaphyseal spurs.
  diagnosis_term:
    preferred_term: bone radiography
    term:
      id: NCIT:C137876
      label: Bone Radiography
  evidence:
  - reference: DOI:10.1007/s40124-024-00315-9
    reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the Frankel sign (dense line at the end of metaphyses from increased width
      at the zone of provisional calcification)
    explanation: >-
      Describes characteristic metaphyseal radiographic signs used to recognize
      skeletal scurvy.
treatments:
- name: Vitamin C Supplementation
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Pharmacologic replacement with L-ascorbic acid (vitamin C) restores
    dioxygenase cofactor activity, rapidly resolving constitutional symptoms
    within days and reversing mucocutaneous hemorrhage and connective tissue
    defects over weeks.
  treatment_term:
    preferred_term: vitamin C supplementation
    term:
      id: NCIT:C15425
      label: Nutritional Supplementation
    therapeutic_agent:
    - preferred_term: L-ascorbic acid
      term:
        id: CHEBI:29073
        label: L-ascorbic acid
  target_mechanisms:
  - target: Defective Collagen Prolyl and Lysyl Hydroxylation
    treatment_effect: RESTORES
    description: >-
      Repletes the L-ascorbic acid cofactor required for prolyl and lysyl
      hydroxylase activity and mature collagen secretion.
    evidence:
    - reference: PMID:37366866
      reference_title: "Scurvy: Rediscovering a Forgotten Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It can be adequately treated and prevented via vitamin C supplementation.
      explanation: >-
        Supports vitamin C supplementation to reverse scorbutic connective
        tissue synthesis failure.
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Vitamin C is essential in converting proline into 3- or
        4- hydroxyproline and in converting lysine to hydroxylysine.
      explanation: >-
        Establishes the collagen prolyl and lysyl hydroxylation reactions
        restored by vitamin C repletion.
  - target: Impaired Carnitine Biosynthesis and Fatty Acid Transport
    treatment_effect: RESTORES
    description: >-
      Restores ascorbate-dependent hydroxylase activity in endogenous carnitine
      biosynthesis.
    evidence:
    - reference: PMID:37366866
      reference_title: "Scurvy: Rediscovering a Forgotten Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It can be adequately treated and prevented via vitamin C supplementation.
      explanation: >-
        Supports vitamin C supplementation to reverse biochemical defects of
        scurvy.
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Lysine, methionine, and multiple hydroxylases are required for carnitine
        biosynthesis and fatty acid transport. In-vitro studies have revealed
        that the hydroxylases require a reductant, of which ascorbic acid is the
        most optimal [2].
      explanation: >-
        Identifies the carnitine-biosynthetic hydroxylases whose optimal
        reductant is restored by ascorbic acid supplementation.
  - target: Impaired Dopamine Beta-Hydroxylase and Norepinephrine Synthesis
    treatment_effect: RESTORES
    description: >-
      Repletes the ascorbic acid electron donor required for dopamine
      beta-hydroxylase-mediated norepinephrine synthesis.
    evidence:
    - reference: PMID:37366866
      reference_title: "Scurvy: Rediscovering a Forgotten Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It can be adequately treated and prevented via vitamin C supplementation.
      explanation: >-
        Supports vitamin C supplementation to reverse clinical and biochemical
        manifestations of scurvy.
    - reference: DOI:10.1007/s40124-024-00315-9
      reference_title: "Vitamin C: Is it Relevant or Obsolete in the Modern Era?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Vitamin C acts as an electron donor for 15 mammalian enzymes. In the
        nervous system, it is essential to dopamine beta-hydroxylase activity.
      explanation: >-
        Identifies nervous-system dopamine beta-hydroxylase activity as directly
        dependent on vitamin C electron donation.
  evidence:
  - reference: PMID:37366866
    reference_title: "Scurvy: Rediscovering a Forgotten Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It can be adequately treated and prevented via vitamin C supplementation.
    explanation: >-
      Confirms that vitamin C supplementation is the definitive treatment and
      preventive measure for scurvy.
notes: >-
  Scurvy is historically recognized among maritime populations deprived of fresh
  produce and persists in modern clinical practice among patients with severely
  selective diets, neurodevelopmental feeding restriction, alcoholism, food
  insecurity, or gastrointestinal malabsorption. Clinical and biochemical
  manifestations are completely reversible upon L-ascorbic acid repletion.
references:
- reference: PMID:29630239
  title: Vitamin C Deficiency.
  tags:
  - StatPearls
- reference: DOI:10.1007/s40124-024-00315-9
  title: 'Vitamin C: Is it Relevant or Obsolete in the Modern Era?'
  findings: []
- reference: DOI:10.1186/s12888-020-02730-w
  title: 'The neuropsychiatric effects of vitamin C deficiency: a systematic review'
  findings: []
- reference: DOI:10.3390/molecules30030748
  title: 'Vitamin C: A Comprehensive Review of Its Role in Health, Disease Prevention,
    and Therapeutic Potential'
  findings: []
- reference: DOI:10.37275/bsm.v8i9.1066
  title: 'Analysis of the Role of Vitamin C Hypovitaminosis in Scurvy on Bone Health:
    A Single Center Observational Study at Dr. Moewardi General Hospital, Surakarta,
    Indonesia'
  findings: []
📚

References & Deep Research

References

5
PMID:29630239
Vitamin C Deficiency.
No top-level findings curated for this source.
DOI:10.1007/s40124-024-00315-9
Vitamin C: Is it Relevant or Obsolete in the Modern Era?
No top-level findings curated for this source.
DOI:10.1186/s12888-020-02730-w
The neuropsychiatric effects of vitamin C deficiency: a systematic review
No top-level findings curated for this source.
DOI:10.3390/molecules30030748
Vitamin C: A Comprehensive Review of Its Role in Health, Disease Prevention, and Therapeutic Potential
No top-level findings curated for this source.
DOI:10.37275/bsm.v8i9.1066
Analysis of the Role of Vitamin C Hypovitaminosis in Scurvy on Bone Health: A Single Center Observational Study at Dr. Moewardi General Hospital, Surakarta, Indonesia
No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Disorder ▸

Disorder

  • Name: Scurvy
  • Category: Nutritional
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 24

Key Pathophysiology Nodes

  • Collagen Synthesis Impairment
  • Vascular Integrity Failure
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/s40124-024-00315-9
  • DOI:10.1016/j.cardiores.2006.05.005
  • DOI:10.1038/s41598-024-56326-5
  • DOI:10.1093/nar/gkac941
  • DOI:10.1182/blood.2019004158
  • DOI:10.1186/s12888-020-02730-w
  • DOI:10.3389/fnut.2023.1265334
  • DOI:10.3390/diseases11020078
  • DOI:10.3390/molecules30030748
  • DOI:10.37275/bsm.v8i9.1066
Falcon ▸
Pathophysiology description (concise overview)
Edison Scientific Literature 23 citations 2026-01-08T14:22:44.926520

Pathophysiology description (concise overview)

Scurvy results from inadequate L-ascorbate (vitamin C), an essential reducing cofactor for multiple non-heme Fe(II)/2-oxoglutarate (2-OG)–dependent dioxygenases and select monooxygenases. The cardinal molecular lesion is failure of collagen post-translational hydroxylation (proline, lysine), which destabilizes the triple helix, impairs cross-linking, and weakens extracellular matrix (ECM). Clinically, this manifests as capillary fragility with bleeding (petechiae, ecchymoses, gingival hemorrhage), poor wound healing, musculoskeletal pain, and characteristic bone/growth plate abnormalities. Ascorbate also supports HIF hydroxylases (EGLN/PHDs, FIH), TET DNA demethylases, dopamine β-hydroxylase (DBH), peptidylglycine α-amidating monooxygenase (PAM), and carnitine biosynthesis, so deficiency can secondarily perturb hypoxia signaling, epigenetic regulation, catecholamine and peptide amidation pathways, and cellular energy metabolism. Tissue vitamin C homeostasis depends on SLC23A1/SLC23A2 (SVCT1/2) and complementary uptake of dehydroascorbic acid (DHA) via GLUT transporters; dietary lack depletes the small total body pool within weeks, producing the clinical picture of scurvy (gastrointestinal and systemic bleeding, mucocutaneous and skeletal features). (gandhi2023scurvyrediscoveringa pages 1-2, gandhi2023scurvyrediscoveringa pages 2-4, ramanujan2024vitamincis pages 7-7)

1. Core Pathophysiology

  • Collagen hydroxylation failure • Ascorbate donates electrons to prolyl and lysyl hydroxylases during collagen biosynthesis; without ascorbate, hydroxyproline/4-hydroxylysine formation is inadequate, preventing triple-helix stability and mature cross-links. “This reaction uses ascorbic acid as an electron donor,” and failure of hydroxylation impairs bone and fibroblast function, tooth development, wound healing, and vessel integrity. (Gandhi 2023, Diseases, May 2023; doi:10.3390/diseases11020078; https://doi.org/10.3390/diseases11020078) (gandhi2023scurvyrediscoveringa pages 2-4)
  • ECM and vascular integrity • Matrix failure in skin and mucosa explains perifollicular hemorrhage, petechiae, ecchymoses, gingival swelling/bleeding, and gastrointestinal bleeding with normal coagulation tests in many patients. (Gandhi 2023) (gandhi2023scurvyrediscoveringa pages 1-2, gandhi2023scurvyrediscoveringa pages 4-5)
  • Bone and growth plate • Deficient osteoid formation and increased bone resorption yield osteopenia/osteoporosis, cortical thinning, metaphyseal changes and growth-plate abnormalities; pediatric scurvy often presents with limb pain, limp or refusal to walk, and characteristic radiologic bands and periosteal changes. (Gandhi 2023; Lu 2023, Front Nutr, Oct 2023; doi:10.3389/fnut.2023.1265334; https://doi.org/10.3389/fnut.2023.1265334) (gandhi2023scurvyrediscoveringa pages 4-5, lu2023scurvyina pages 2-3)
  • Hypoxia/epigenetic enzyme effects • Ascorbate supports Fe(II)/2-OG dioxygenases beyond collagen: HIF prolyl hydroxylases (EGLN1/2/3) and the asparaginyl hydroxylase FIH regulate HIF; ascorbate helps maintain their catalytic cycles, so deficiency can dysregulate HIF activity. TET dioxygenases (TET1–3) require ascorbate to promote DNA demethylation; low vitamin C may contribute to aberrant methylation. (Fandrey 2006, Cardiovasc Res, Sep 2006; doi:10.1016/j.cardiores.2006.05.005; https://doi.org/10.1016/j.cardiores.2006.05.005; Yue & Rao 2020, Blood, Sep 2020; doi:10.1182/blood.2019004158; https://doi.org/10.1182/blood.2019004158) (ramanujan2024vitamincis pages 7-7, alberts2025vitaminca pages 1-2)
  • Neurochemical and energy pathways • DBH uses ascorbate to convert dopamine to norepinephrine; vitamin C deficiency therefore can lower NE synthesis, contributing to fatigue, mood/cognitive symptoms and autonomic complaints. Ascorbate also serves as electron donor for carnitine biosynthesis steps; deficiency can reduce carnitine availability and worsen fatigue. (Gandhi 2023; Plevin & Galletly 2020, BMC Psychiatry, Jun 2020; doi:10.1186/s12888-020-02730-w; https://doi.org/10.1186/s12888-020-02730-w) (gandhi2023scurvyrediscoveringa pages 2-4, gandhi2023scurvyrediscoveringa pages 4-5)

2. Key Molecular Players

  • Genes/Proteins (HGNC): Prolyl 4-hydroxylase (P4HA1/2/3); Lysyl hydroxylase (PLOD1/2/3); EGLN1/2/3 (PHD1–3); HIF1AN (FIH); TET1/2/3; DBH; PAM; TMLHE/BBOX1 (carnitine biosynthesis); SLC23A1/2 (SVCT1/2); SLC2A family (GLUTs for DHA). Mechanistic roles and evidence mapping are synthesized in the artifact below. (ramanujan2024vitamincis pages 7-7, gandhi2023scurvyrediscoveringa pages 2-4, alberts2025vitaminca pages 1-2)
  • Chemical Entities (CHEBI): L‑ascorbate; dehydroascorbic acid; dopamine; norepinephrine; carnitine. (gandhi2023scurvyrediscoveringa pages 2-4, lu2023scurvyina pages 2-3)
  • Cell Types (CL): Fibroblasts (collagen production), endothelial cells (capillary integrity), osteoblasts and chondrocytes (osteoid and growth plate matrix). (gandhi2023scurvyrediscoveringa pages 4-5)
  • Anatomical Locations (UBERON): Skin, gingiva, bone, epiphyseal (growth) plate, GI mucosa. (gandhi2023scurvyrediscoveringa pages 4-5, gandhi2023scurvyrediscoveringa pages 1-2)
Category Entity Name Ontology ID / Abbrev Role in Scurvy Pathophysiology (1-2 sentences) Evidence
Enzyme Prolyl 4-hydroxylase alpha subunits (P4HA1/2/3) HGNC:P4HA1/P4HA2/P4HA3 Hydroxylate proline residues in procollagen to enable triple-helix formation; impaired activity from ascorbate deficiency destabilizes collagen and weakens ECM, causing bleeding and poor wound healing. (ramanujan2024vitamincis pages 7-7, gandhi2023scurvyrediscoveringa pages 2-4)
Enzyme Lysyl hydroxylases (PLOD1/2/3) HGNC:PLOD1/PLOD2/PLOD3 Hydroxylate lysine residues required for collagen cross-linking; deficiency reduces crosslinks leading to fragile connective tissue and defective bone matrix. (ramanujan2024vitamincis pages 7-7, gandhi2023scurvyrediscoveringa pages 2-4)
Enzyme (oxygen sensor) HIF prolyl hydroxylases (EGLN1/2/3, a.k.a. PHD1/2/3) HGNC:EGLN1/EGLN2/EGLN3 2‑OG/Fe(II)-dependent prolyl hydroxylases that regulate HIF stability; ascorbate maintains enzyme activity so deficiency can dysregulate hypoxia signaling. (ramanujan2024vitamincis pages 7-7)
Enzyme (regulator) Factor inhibiting HIF (HIF1AN / FIH) HGNC:HIF1AN Asparaginyl hydroxylase that modulates HIF transcriptional activity; requires reducing cofactor activity supported by ascorbate, so deficiency can alter HIF transcriptional outputs. (ramanujan2024vitamincis pages 7-7)
Enzyme (epigenetic) TET1 / TET2 / TET3 HGNC:TET1/TET2/TET3 Fe(II)/2‑OG dioxygenases that oxidize 5mC to 5hmC promoting active DNA demethylation; ascorbate is a cofactor and deficiency may impair epigenetic regulation. (alberts2025vitaminca pages 1-2, gandhi2023scurvyrediscoveringa pages 2-4)
Enzyme (catecholamine) Dopamine beta-hydroxylase (DBH) HGNC:DBH Converts dopamine → norepinephrine within secretory vesicles using ascorbate as electron donor; deficiency can reduce NE synthesis and contribute to neuropsychiatric/autonomic features. (gandhi2023scurvyrediscoveringa pages 2-4, ramanujan2024vitamincis pages 7-7)
Enzyme (peptide maturation) Peptidylglycine alpha-amidating monooxygenase (PAM) HGNC:PAM Amidating monooxygenase requiring ascorbate for peptide hormone/neuropeptide maturation; deficiency may impair peptide signaling. (gandhi2023scurvyrediscoveringa pages 2-4, ramanujan2024vitamincis pages 7-7)
Enzymes (carnitine biosynthesis) TMLHE, BBOX1 HGNC:TMLHE, BBOX1 Ascorbate-dependent dioxygenase steps in carnitine biosynthesis; deficiency can reduce carnitine levels and contribute to muscle fatigue. (gandhi2023scurvyrediscoveringa pages 2-4, lu2023scurvyina pages 2-3)
Transporter Vitamin C transporters (SLC23A1 / SLC23A2; SVCT1/2) HGNC:SLC23A1, SLC23A2 Sodium-dependent vitamin C transporters mediate ascorbate uptake and tissue accumulation; altered expression or saturation affects tissue ascorbate and scurvy susceptibility. (ramanujan2024vitamincis pages 7-7)
Transporter (alternative) DHA transport via GLUTs (SLC2A family) HGNC:SLC2A* (GLUTs) Oxidized form dehydroascorbic acid (DHA) can be transported via GLUT family members and reduced intracellularly to ascorbate, providing an alternative uptake route. (gandhi2023scurvyrediscoveringa pages 2-4, ramanujan2024vitamincis pages 7-7)
Structural protein / GO Collagen (generic) GO:0005581 (extracellular matrix) Principal ECM protein requiring prolyl/lysyl hydroxylation for structural stability; defective collagen underlies capillary fragility, mucosal bleeding, poor wound healing, and defective bone matrix. (gandhi2023scurvyrediscoveringa pages 2-4, lu2023scurvyina pages 2-3)
Cell type (CL) Fibroblast CL:Fibroblast Major collagen-producing stromal cell; impaired collagen processing in fibroblasts leads to weakened dermal and connective tissues seen in scurvy. (gandhi2023scurvyrediscoveringa pages 2-4, ramanujan2024vitamincis pages 7-7)
Cell type (CL) Osteoblast CL:Osteoblast Bone-forming cells that produce osteoid rich in type I collagen; defective collagen synthesis impairs osteoid formation, causing osteoporosis, cortical thinning, and growth-plate pathology. (gandhi2023scurvyrediscoveringa pages 4-5, nefihancoro2024analysisofthe pages 4-7)
Cell type (CL) Chondrocyte CL:Chondrocyte Cartilage/growth-plate cells that depend on collagen-rich matrix; ascorbate deficiency impairs endochondral matrix formation producing metaphyseal and epiphyseal abnormalities. (gandhi2023scurvyrediscoveringa pages 4-5, lu2023scurvyina pages 2-3)
Cell type (CL) Endothelial cell CL:Endothelial cell Vascular integrity relies on collagen-containing basement membrane; impaired collagen leads to capillary fragility and hemorrhage (petechiae, ecchymoses). (gandhi2023scurvyrediscoveringa pages 2-4, gandhi2023scurvyrediscoveringa pages 1-2)
Anatomy (UBERON) Gingiva UBERON:Gingiva Highly vascular mucosa with collagen-rich stroma; scurvy causes gingival swelling, bleeding, and periodontal disease due to ECM failure. (gandhi2023scurvyrediscoveringa pages 2-4, lu2023scurvyina pages 2-3)
Anatomy (UBERON) Skin UBERON:Skin Dermal ECM failure causes perifollicular hemorrhages, petechiae, and poor wound healing characteristic of scurvy. (gandhi2023scurvyrediscoveringa pages 4-5, gandhi2023scurvyrediscoveringa pages 2-4)
Anatomy (UBERON) Bone UBERON:Bone Impaired collagen in osteoid leads to brittle bones, osteoporosis, cortical thinning, and fracture risk in scurvy. (nefihancoro2024analysisofthe pages 4-7, gandhi2023scurvyrediscoveringa pages 4-5)
Anatomy (UBERON) Epiphyseal (growth) plate UBERON:Epiphyseal_plate Collagen-dependent cartilage zone for endochondral ossification; deficiency produces growth-plate abnormalities, metaphyseal bands, and limp/pseudoparalysis in children. (gandhi2023scurvyrediscoveringa pages 4-5, lu2023scurvyina pages 2-3)
Chemical (CHEBI) L-ascorbate (vitamin C) CHEBI:Asc Essential reducing cofactor for multiple Fe(II)/2‑OG dioxygenases and antioxidant; insufficient levels cause scurvy. (gandhi2023scurvyrediscoveringa pages 1-2, ramanujan2024vitamincis pages 7-7)
Chemical (CHEBI) Dehydroascorbic acid (DHA) CHEBI:DHA Oxidized form of ascorbate transported via GLUTs and reduced intracellularly to regenerate ascorbate; important alternative uptake pathway. (gandhi2023scurvyrediscoveringa pages 2-4, ramanujan2024vitamincis pages 7-7)
Chemical (CHEBI) Dopamine CHEBI:Dopamine Catecholamine precursor converted by DBH to norepinephrine using ascorbate; impaired DBH activity can alter neurotransmitter balance. (gandhi2023scurvyrediscoveringa pages 2-4, ramanujan2024vitamincis pages 7-7)
Chemical (CHEBI) Norepinephrine CHEBI:Norepinephrine Product of DBH; reduced synthesis in severe ascorbate deficiency may contribute to autonomic and neuropsychiatric symptoms. (gandhi2023scurvyrediscoveringa pages 2-4, ramanujan2024vitamincis pages 7-7)
Chemical (CHEBI) Carnitine CHEBI:Carnitine Requires ascorbate-dependent enzymatic steps for biosynthesis; deficiency can impair fatty acid transport into mitochondria and produce fatigue/weakness. (gandhi2023scurvyrediscoveringa pages 2-4, lu2023scurvyina pages 2-3)

Table: A concise reference table mapping enzymes, cells, tissues, and chemicals relevant to scurvy to ontology identifiers, their roles in pathophysiology, and the supporting evidence (context IDs). This facilitates ontology-driven annotation and rapid linking of mechanisms to sources.

3. Biological Processes (GO) disrupted

  • Collagen biosynthetic process and post-translational modification (proline/lysine hydroxylation; triple-helix formation; cross-linking); ECM organization; wound healing; angiogenesis and vascular integrity. (Gandhi 2023) (gandhi2023scurvyrediscoveringa pages 2-4, gandhi2023scurvyrediscoveringa pages 4-5)
  • Cellular responses to hypoxia; regulation of HIF signaling by prolyl/asparaginyl hydroxylation (EGLN/PHDs; FIH). (Fandrey 2006) (ramanujan2024vitamincis pages 7-7)
  • DNA demethylation via TET-mediated oxidation of 5-mC to 5-hmC; epigenetic regulation of immune and lineage programs. (Yue & Rao 2020; Morante-Palacios 2022, Nucleic Acids Res, Oct 2022; doi:10.1093/nar/gkac941; https://doi.org/10.1093/nar/gkac941) (alberts2025vitaminca pages 1-2, ramanujan2024vitamincis pages 7-8)
  • Catecholamine biosynthetic process (DBH step dopamine→norepinephrine); peptide amidation (PAM); carnitine biosynthetic process. (Gandhi 2023; Plevin 2020) (gandhi2023scurvyrediscoveringa pages 2-4, gandhi2023scurvyrediscoveringa pages 4-5)

4. Cellular Components affected

  • Endoplasmic reticulum lumen and cisternae (collagen prolyl/lysyl hydroxylases act co-translationally/post-translationally on procollagen); secretory pathway/extracellular space (ECM deposition). (Gandhi 2023) (gandhi2023scurvyrediscoveringa pages 2-4)
  • Nucleus/chromatin (TET-mediated DNA demethylation); cytosol and mitochondria (carnitine metabolism); secretory vesicles (DBH in catecholaminergic vesicles). (Yue 2020; Plevin 2020) (alberts2025vitaminca pages 1-2, gandhi2023scurvyrediscoveringa pages 4-5)

5. Disease Progression

  • Trigger and depletion: Humans lack GULO and must ingest vitamin C; limited body pool (approx. 1–3 weeks to deplete on very low intake) and saturable gut/renal handling cause rapid deficiency under poor diet/malabsorption. (Gandhi 2023) (gandhi2023scurvyrediscoveringa pages 1-2)
  • Early biochemical failure: Insufficient ascorbate disrupts collagen hydroxylation, compromising ECM repair and capillary integrity; fatigue may occur early via reduced catecholamines and carnitine. (Lu 2023; Gandhi 2023) (lu2023scurvyina pages 2-3, gandhi2023scurvyrediscoveringa pages 2-4)
  • Clinical evolution: Within 4–12 weeks of inadequate intake, nonspecific symptoms progress to gingival bleeding, perifollicular hemorrhages, ecchymoses, joint pain/hemarthrosis, and in children, limb pain and refusal to walk due to metaphyseal and periosteal changes. (Gandhi 2023) (gandhi2023scurvyrediscoveringa pages 4-5)
  • Advanced skeletal involvement: Osteoporosis and cortical thinning correlate with severity; growth-plate pathology and fractures may occur if untreated. (Nefihancoro 2024, Bioscientia Medicina, Jun 2024; doi:10.37275/bsm.v8i9.1066; https://doi.org/10.37275/bsm.v8i9.1066) (nefihancoro2024analysisofthe pages 4-7)
  • Reversibility: Vitamin C repletion rapidly reverses constitutional and bleeding symptoms; musculoskeletal recovery follows over weeks. (Lu 2023) (lu2023scurvyina pages 2-3)

6. Phenotypic Manifestations and mechanistic links

  • Mucocutaneous: Perifollicular hemorrhages, petechiae, ecchymoses, corkscrew hairs, gingival swelling/bleeding—due to fragile capillaries and ECM failure from defective collagen. (Gandhi 2023) (gandhi2023scurvyrediscoveringa pages 4-5)
  • Musculoskeletal: Arthralgias, hemarthrosis, muscle hematomas; in children, limp/refusal to walk; radiologic metaphyseal bands, periosteal reaction, and osteopenia—reflecting defective osteoid/calcified cartilage matrix. (Gandhi 2023) (gandhi2023scurvyrediscoveringa pages 4-5)
  • Gastrointestinal: Occult or overt bleeding due to mucosal/vascular fragility. (Gandhi 2023) (gandhi2023scurvyrediscoveringa pages 1-2)
  • Neuropsychiatric: Fatigue, depression, cognitive complaints are reported in deficiency; biologically linked to decreased NE synthesis (DBH cofactor role) and broader neurotransmitter/antioxidant roles. (Plevin 2020) (gandhi2023scurvyrediscoveringa pages 4-5)

Evidence items (with selected direct quotations)

  • “This reaction uses ascorbic acid as an electron donor,” referring to hydroxylation of proline and lysine residues in collagen; failure of hydroxylation impairs bone and fibroblast function, tooth development, wound healing, and vessel integrity. (Gandhi 2023, Diseases, May 2023; https://doi.org/10.3390/diseases11020078) (gandhi2023scurvyrediscoveringa pages 2-4)
  • Pediatric skeletal presentation: review and MRI/radiograph features (periosteal reaction, metaphyseal bands, refusal to walk) summarized in Gandhi 2023. (gandhi2023scurvyrediscoveringa pages 4-5)
  • Observational 2024 bone study: “Radiological examination shows significant changes in long bones, especially osteoporosis and thinning of the cortex... positive correlation between the severity of scurvy and the incidence of osteoporosis (rho = 0.495, p = 0.005) and cortical thinning (rho = 0.394, p = 0.031).” (Nefihancoro 2024; https://doi.org/10.37275/bsm.v8i9.1066) (nefihancoro2024analysisofthe pages 4-7)
  • TET and vitamin C: Vitamin C “serves as a cofactor for Fe(II) and 2-oxoglutarate (2OG)-dependent dioxygenases including TET family enzymes,” promoting DNA demethylation. (Yue & Rao 2020, Blood; https://doi.org/10.1182/blood.2019004158) (alberts2025vitaminca pages 1-2)
  • HIF hydroxylases: Mechanistic role of ascorbate in preserving prolyl hydroxylase activity and regulating HIF signaling reviewed by Fandrey et al. (Cardiovasc Res 2006; https://doi.org/10.1016/j.cardiores.2006.05.005) (ramanujan2024vitamincis pages 7-7)
  • Immune/epigenetic reprogramming: Vitamin C enhances NF-κB–driven epigenomic remodeling in dendritic cells via TET2, boosting antigen presentation. (Morante‑Palacios 2022; https://doi.org/10.1093/nar/gkac941) (ramanujan2024vitamincis pages 7-8)

Current applications and real‑world implementations

  • Clinical detection and radiology • Recent case reports and observational data (2023–2024) emphasize that scurvy should be considered in patients with unexplained mucocutaneous bleeding and musculoskeletal pain; radiographs/MRI can reveal metaphyseal bands, periosteal reactions, osteopenia, and cortical thinning that improve with repletion. (Lu 2023; Nefihancoro 2024) (lu2023scurvyina pages 2-3, nefihancoro2024analysisofthe pages 4-7)
  • Risk stratification and transporters • Contemporary pediatric review synthesizes transporter biology (SLC23A1/2; DHA uptake via GLUTs) and vulnerable populations (e.g., chronic disease, critical illness), informing screening and supplementation strategies. (Ramanujan 2024, Curr Pediatr Rep, May 2024; https://doi.org/10.1007/s40124-024-00315-9) (ramanujan2024vitamincis pages 7-8, ramanujan2024vitamincis pages 7-7)

Expert opinions and analysis

  • Consensus from recent reviews supports a central role for ascorbate in collagen hydroxylation and broader dioxygenase biology, with clinical scurvy arising from ECM failure and secondarily from dysregulated hypoxia and epigenetic pathways in some contexts. (Gandhi 2023; Ramanujan 2024; Yue 2020) (gandhi2023scurvyrediscoveringa pages 2-4, ramanujan2024vitamincis pages 7-8, alberts2025vitaminca pages 1-2)
  • The 2024 observational bone study underscores that scurvy still presents with significant skeletal morbidity; systematic radiological assessment and prompt vitamin C repletion can mitigate complications. (Nefihancoro 2024) (nefihancoro2024analysisofthe pages 4-7)

Relevant statistics and data (recent)

  • Nefihancoro 2024 (Indonesia, 2020–2023; n=30): fatigue 86.7%, joint pain 73.3%, bleeding gums 60%, skin bleeding 53.3%; radiology showed osteoporosis and cortical thinning with severity; Spearman correlations: osteoporosis rho=0.495 (p=0.005), cortical thinning rho=0.394 (p=0.031). (https://doi.org/10.37275/bsm.v8i9.1066) (nefihancoro2024analysisofthe pages 4-7)
  • Pediatric presentation patterns summarized across recent literature (limp/refusal to walk ~one-third; musculoskeletal complaints ~90% in children). (Gandhi 2023) (gandhi2023scurvyrediscoveringa pages 4-5)

Gene/protein annotations with ontology terms

  • HGNC: P4HA1/2/3; PLOD1/2/3; EGLN1/2/3; HIF1AN; TET1/2/3; DBH; PAM; TMLHE; BBOX1; SLC23A1/SLC23A2; SLC2A family. (ramanujan2024vitamincis pages 7-7, alberts2025vitaminca pages 1-2)
  • GO processes: collagen biosynthetic process; extracellular matrix organization; wound healing; response to hypoxia; DNA demethylation; catecholamine biosynthetic process; peptide amidation; carnitine biosynthetic process. (gandhi2023scurvyrediscoveringa pages 2-4, ramanujan2024vitamincis pages 7-7, alberts2025vitaminca pages 1-2)
  • Cellular components: endoplasmic reticulum lumen; secretory vesicle; extracellular matrix; chromatin. (gandhi2023scurvyrediscoveringa pages 2-4, alberts2025vitaminca pages 1-2)

Phenotype associations (HP terms; narrative mapping)

  • Mucocutaneous bleeding (petechiae, ecchymoses), gingival hypertrophy/bleeding, poor wound healing, perifollicular hemorrhages; musculoskeletal pain/hemarthrosis; pediatric limp/refusal to walk; osteopenia/osteoporosis; cortical thinning; metaphyseal bands and periosteal reaction on imaging. Mechanistic links: collagen hydroxylation failure → ECM weakness and capillary fragility; impaired osteoid matrix. (gandhi2023scurvyrediscoveringa pages 4-5, nefihancoro2024analysisofthe pages 4-7)

Cell type involvement (CL terms; narrative mapping)

  • Fibroblasts (dermal ECM); endothelial cells (capillary walls); osteoblasts and chondrocytes (bone/growth plate matrix); immune dendritic cells (ascorbate-dependent TET reprogramming). (gandhi2023scurvyrediscoveringa pages 4-5, ramanujan2024vitamincis pages 7-8)

Anatomical locations (UBERON; narrative mapping)

  • Skin, gingiva, bone, epiphyseal (growth) plate, gastrointestinal mucosa. (gandhi2023scurvyrediscoveringa pages 4-5, gandhi2023scurvyrediscoveringa pages 1-2)

Chemical entities (CHEBI; narrative mapping)

  • L‑ascorbate, dehydroascorbic acid (DHA), dopamine, norepinephrine, carnitine. (gandhi2023scurvyrediscoveringa pages 2-4, lu2023scurvyina pages 2-3)

Transport and tissue distribution

  • Active intestinal uptake and renal handling are saturable; dehydroascorbic acid can “passively penetrate cellular membranes” and is preferentially taken up by erythrocytes and leukocytes (DHA → ascorbate intracellular reduction). SLC23A1/SLC23A2 (SVCT1/2) underlie systemic/tissue accumulation; decreased plasma ascorbate with compensatory changes in SLC23A1/2 expression is observed in disease states, underscoring reliance on these transporters. (Gandhi 2023; Ramanujan 2024; Linowiecka 2024, Sci Rep, Mar 2024; doi:10.1038/s41598-024-56326-5; https://doi.org/10.1038/s41598-024-56326-5) (gandhi2023scurvyrediscoveringa pages 2-4, ramanujan2024vitamincis pages 7-8, ramanujan2024vitamincis pages 7-7)

References with URLs and dates (selected)

  • Gandhi M et al. Scurvy: Rediscovering a Forgotten Disease. Diseases. May 2023. doi:10.3390/diseases11020078. https://doi.org/10.3390/diseases11020078 (gandhi2023scurvyrediscoveringa pages 1-2, gandhi2023scurvyrediscoveringa pages 2-4, gandhi2023scurvyrediscoveringa pages 4-5)
  • Lu R-L et al. Scurvy in a young man: a rare case report. Front Nutr. Oct 2023. doi:10.3389/fnut.2023.1265334. https://doi.org/10.3389/fnut.2023.1265334 (lu2023scurvyina pages 2-3)
  • Nefihancoro UH, Faisal R. Analysis of the Role of Vitamin C Hypovitaminosis in Scurvy on Bone Health. Bioscientia Medicina. Jun 2024. doi:10.37275/bsm.v8i9.1066. https://doi.org/10.37275/bsm.v8i9.1066 (nefihancoro2024analysisofthe pages 4-7)
  • Ramanujan S et al. Vitamin C: Is it Relevant or Obsolete in the Modern Era? Curr Pediatr Rep. May 2024. doi:10.1007/s40124-024-00315-9. https://doi.org/10.1007/s40124-024-00315-9 (ramanujan2024vitamincis pages 7-8, ramanujan2024vitamincis pages 7-7)
  • Yue X, Rao A. TET family dioxygenases and the TET activator vitamin C in immune responses and cancer. Blood. Sep 2020. doi:10.1182/blood.2019004158. https://doi.org/10.1182/blood.2019004158 (alberts2025vitaminca pages 1-2)
  • Morante‑Palacios O et al. Vitamin C enhances NF‑κB‑driven epigenomic reprogramming… Nucleic Acids Res. Oct 2022. doi:10.1093/nar/gkac941. https://doi.org/10.1093/nar/gkac941 (ramanujan2024vitamincis pages 7-8)
  • Fandrey J et al. Regulating cellular oxygen sensing by hydroxylation. Cardiovasc Res. Sep 2006. doi:10.1016/j.cardiores.2006.05.005. https://doi.org/10.1016/j.cardiores.2006.05.005 (ramanujan2024vitamincis pages 7-7)
  • Plevin D, Galletly C. The neuropsychiatric effects of vitamin C deficiency: a systematic review. BMC Psychiatry. Jun 2020. doi:10.1186/s12888-020-02730-w. https://doi.org/10.1186/s12888-020-02730-w (gandhi2023scurvyrediscoveringa pages 4-5)

Notes on evidence strength and recency: We prioritized 2023–2024 clinical and review literature for modern presentations and radiologic skeletal data (Gandhi 2023; Lu 2023; Nefihancoro 2024; Ramanujan 2024). Mechanistic underpinnings referencing ascorbate’s enzymology and transporter biology are supported by these recent reviews and by established mechanistic reviews on HIF/TET dioxygenases (Fandrey 2006; Yue 2020; Morante‑Palacios 2022). Where possible, we included direct quotations for key mechanistic claims and provided DOI/URL and publication dates. (gandhi2023scurvyrediscoveringa pages 2-4, nefihancoro2024analysisofthe pages 4-7, ramanujan2024vitamincis pages 7-8, alberts2025vitaminca pages 1-2, ramanujan2024vitamincis pages 7-7)

References

  1. (gandhi2023scurvyrediscoveringa pages 1-2): Mustafa Gandhi, Omar Elfeky, Hamza Ertugrul, Harleen Kaur Chela, and Ebubekir Daglilar. Scurvy: rediscovering a forgotten disease. Diseases, 11:78, May 2023. URL: https://doi.org/10.3390/diseases11020078, doi:10.3390/diseases11020078. This article has 82 citations and is from a poor quality or predatory journal.

  2. (gandhi2023scurvyrediscoveringa pages 2-4): Mustafa Gandhi, Omar Elfeky, Hamza Ertugrul, Harleen Kaur Chela, and Ebubekir Daglilar. Scurvy: rediscovering a forgotten disease. Diseases, 11:78, May 2023. URL: https://doi.org/10.3390/diseases11020078, doi:10.3390/diseases11020078. This article has 82 citations and is from a poor quality or predatory journal.

  3. (ramanujan2024vitamincis pages 7-7): Suruchi Ramanujan, Sanu Yadav, Andrea Adler, Sara Bewley, and Kadakkal Radhakrishnan. Vitamin c: is it relevant or obsolete in the modern era? Current Pediatrics Reports, 12:35-43, May 2024. URL: https://doi.org/10.1007/s40124-024-00315-9, doi:10.1007/s40124-024-00315-9. This article has 6 citations.

  4. (gandhi2023scurvyrediscoveringa pages 4-5): Mustafa Gandhi, Omar Elfeky, Hamza Ertugrul, Harleen Kaur Chela, and Ebubekir Daglilar. Scurvy: rediscovering a forgotten disease. Diseases, 11:78, May 2023. URL: https://doi.org/10.3390/diseases11020078, doi:10.3390/diseases11020078. This article has 82 citations and is from a poor quality or predatory journal.

  5. (lu2023scurvyina pages 2-3): Rui-Ling Lu, Jie-Wen Guo, Bao-dong Sun, Yu-Lan Chen, and Dong-Zhou Liu. Scurvy in a young man: a rare case report. Frontiers in Nutrition, Oct 2023. URL: https://doi.org/10.3389/fnut.2023.1265334, doi:10.3389/fnut.2023.1265334. This article has 7 citations and is from a poor quality or predatory journal.

  6. (alberts2025vitaminca pages 1-2): Adina Alberts, Elena-Theodora Moldoveanu, Adelina-Gabriela Niculescu, and Alexandru Mihai Grumezescu. Vitamin c: a comprehensive review of its role in health, disease prevention, and therapeutic potential. Molecules, 30:748, Feb 2025. URL: https://doi.org/10.3390/molecules30030748, doi:10.3390/molecules30030748. This article has 75 citations and is from a poor quality or predatory journal.

  7. (nefihancoro2024analysisofthe pages 4-7): Udi Heru Nefihancoro and Rachmad Faisal. Analysis of the role of vitamin c hypovitaminosis in scurvy on bone health: a single center observational study at dr. moewardi general hospital, surakarta, indonesia. Bioscientia Medicina : Journal of Biomedicine and Translational Research, 8:4894-4902, Jun 2024. URL: https://doi.org/10.37275/bsm.v8i9.1066, doi:10.37275/bsm.v8i9.1066. This article has 0 citations.

  8. (ramanujan2024vitamincis pages 7-8): Suruchi Ramanujan, Sanu Yadav, Andrea Adler, Sara Bewley, and Kadakkal Radhakrishnan. Vitamin c: is it relevant or obsolete in the modern era? Current Pediatrics Reports, 12:35-43, May 2024. URL: https://doi.org/10.1007/s40124-024-00315-9, doi:10.1007/s40124-024-00315-9. This article has 6 citations.