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Cadmium Poisoning

Environmental MONDO:0043523 heavy metal poisoning

Cadmium poisoning is a toxic condition resulting from acute or chronic exposure to cadmium, a heavy metal encountered primarily through occupational sources (silver jewelry industry, zinc smelting, battery manufacturing), contaminated food and water, and tobacco smoke. Acute inhalation of cadmium fumes causes severe pneumonitis and acute lung injury. Chronic exposure leads to progressive renal tubular dysfunction (Fanconi syndrome), hypophosphataemic osteomalacia, osteoporosis, and peripheral neuropathy. The most severe form of chronic cadmium toxicity is itai-itai disease, endemic in cadmium-polluted regions of Japan, characterized by severe bone pain, fractures, and renal failure. Cadmium has a long biological half-life (10-30 years) and there is no effective antidote; management centers on exposure cessation, chelation therapy, and supportive care.

0
Mappings
0
Definitions
0
Inheritance
14
Pathophysiology
5
Histopathology
9
Phenotypes
0
Genes
5
Treatments
2
Subtypes
5
Differentials
1
Datasets
4
Trials
◆

Subtypes

2
Acute Cadmium Poisoning (Inhalation)
Acute cadmium poisoning from inhalation of cadmium fumes or dust, typically occurring in occupational settings (welding, smelting, silver jewelry manufacturing). Presents with acute lung injury, chemical pneumonitis, pulmonary edema, and potentially fatal respiratory failure. Symptoms may be delayed 12-36 hours after exposure.
Show evidence (2 references)
PMID:16933734 SUPPORT Human Clinical
"Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
Confirms acute cadmium inhalation as a cause of acute lung injury.
PMID:41000307 SUPPORT Human Clinical
"For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required."
Systematic review confirms severe acute presentations requiring ventilatory support.
Chronic Cadmium Poisoning (Itai-itai Disease)
Chronic cadmium toxicity from prolonged low-level exposure via contaminated food, water, or occupational sources. Characterized by progressive renal tubular dysfunction, Fanconi syndrome, hypophosphataemic osteomalacia, osteoporosis, and pathologic fractures. Itai-itai disease represents the most severe form, endemic in cadmium-polluted areas of Japan.
Show evidence (2 references)
PMID:39111871 SUPPORT Human Clinical
"Itai-itai disease is the most severe case of chronic cadmium (Cd) toxicity, which was endemic in Cd-polluted areas in the Jinzu River basin in Toyama prefecture, Japan."
Describes itai-itai disease as the most severe form of chronic cadmium toxicity.
PMID:23800513 SUPPORT Human Clinical
"He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure."
Case report confirming chronic cadmium toxicity from occupational exposure with renal and skeletal manifestations.
⚙

Pathophysiology

14
Cadmium Absorption and Systemic Distribution
Cadmium enters the body via inhalation of fumes/dust or gastrointestinal absorption from contaminated food and water. Inhaled cadmium has 25-50% bioavailability; oral absorption is lower (3-8%) but enhanced by iron deficiency via shared divalent metal transporter 1 (DMT1). Once absorbed, cadmium distributes via the bloodstream bound to albumin and accumulates in liver, kidney, and bone with a biological half-life of 10-30 years.
cellular response to cadmium ion link
Show evidence (5 references)
PMID:23800513 SUPPORT Human Clinical
"Cadmium has a long biological half-life and there is no effective treatment for people who are exposed to it."
Confirms cadmium's long biological half-life contributing to progressive systemic accumulation.
PMID:22349354 SUPPORT Human Clinical
"In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
Autopsy findings confirm systemic cadmium distribution to multiple organs.
PMID:41000307 SUPPORT Human Clinical
"The study also found that low iron stores exacerbate cadmium poisoning."
Confirms that iron deficiency enhances cadmium absorption via shared transport mechanisms.
+ 2 more references
Hepatic Metallothionein Binding
The liver is the primary site of initial cadmium detoxification. Hepatocytes synthesize metallothionein (MT), a cysteine-rich protein that binds cadmium with high affinity. The cadmium-metallothionein (Cd-MT) complex is slowly released into the bloodstream over time. While MT binding initially protects against free cadmium toxicity, the Cd-MT complex is filtered at the glomerulus and taken up by renal tubular cells, effectively transferring the cadmium burden to the kidney.
hepatocyte link
detoxification of inorganic compound link
liver link
Show evidence (2 references)
PMID:25042840 SUPPORT Model Organism
"This half-life is partly as a result of metallothioneins (MTs), metal-binding proteins with a high affinity for Cd."
Confirms metallothionein as the primary cadmium-binding protein responsible for cadmium's long biological half-life.
PMID:20354761 SUPPORT Human Clinical
"The kidney is the main organ affected by chronic Cd exposure and toxicity. Cd accumulates in the kidney as a result of its preferential uptake by receptor-mediated endocytosis of freely filtered and metallothionein bound Cd (Cd-MT) in the renal proximal tubule."
Review confirms that hepatically-produced Cd-MT is filtered and taken up by the kidney, establishing the liver-to-kidney transfer pathway.
Renal Proximal Tubular Cadmium Uptake
The cadmium-metallothionein (Cd-MT) complex is freely filtered at the glomerulus due to its small molecular weight (~7 kDa). Proximal tubular epithelial cells reabsorb Cd-MT via receptor-mediated endocytosis through the megalin/cubilin receptor complex. Once internalized, Cd-MT is degraded in lysosomes, releasing free cadmium ions intracellularly. This mechanism explains the kidney's particular vulnerability to cadmium accumulation.
proximal tubule cell link
receptor-mediated endocytosis link
proximal tubule link
Show evidence (4 references)
PMID:20204475 SUPPORT Human Clinical
"the multiligand endocytic receptors megalin and cubilin take up cadmium-metallothionein complexes via receptor-mediated endocytosis."
Demonstrates that megalin and cubilin receptors mediate the endocytic uptake of Cd-MT complexes in proximal tubule.
PMID:34298880 SUPPORT Model Organism
"Cd2+ complexed to metallothionein (MT) (CdMT) is taken up through receptor-mediated endocytosis (RME) via the PT receptor megalin:cubilin, which is the predominant pathway for reuptake of filtered proteins in the kidney."
Confirms megalin:cubilin as the predominant receptor for Cd-MT uptake in proximal tubule.
PMID:20354761 SUPPORT Human Clinical
"Cd accumulates in the kidney as a result of its preferential uptake by receptor-mediated endocytosis of freely filtered and metallothionein bound Cd (Cd-MT) in the renal proximal tubule. Internalised Cd-MT is degraded in endosomes and lysosomes, releasing free Cd(2+) into the cytosol"
Review details the full Cd-MT uptake pathway: glomerular filtration, receptor-mediated endocytosis, lysosomal degradation, and free Cd2+ release.
+ 1 more reference
Proximal Tubular Cell Injury
When intracellular cadmium exceeds the metallothionein binding capacity of proximal tubular cells (typically at renal cortex concentrations above 200 mcg/g), free cadmium ions cause oxidative stress, mitochondrial dysfunction, and activation of apoptotic pathways. Cadmium displaces zinc from zinc-finger proteins and disrupts calcium signaling, leading to tubular cell death.
proximal tubule cell link
apoptotic process link ↑ INCREASED
proximal tubule link
Show evidence (2 references)
PMID:39111871 SUPPORT Human Clinical
"She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."
Documents advanced renal tubular dysfunction resulting from proximal tubular cell injury in chronic cadmium exposure.
PMID:20354761 SUPPORT Human Clinical
"Internalised Cd-MT is degraded in endosomes and lysosomes, releasing free Cd(2+) into the cytosol, where it can generate reactive oxygen species (ROS) and activate cell death pathways."
Review details the mechanism of tubular cell injury: lysosomal release of free Cd2+ generates ROS and activates apoptosis.
Impaired Tubular Reabsorption
Injury to proximal tubular cells causes Fanconi syndrome, characterized by impaired reabsorption of low-molecular-weight proteins (beta-2- microglobulin, retinol-binding protein), glucose, amino acids, uric acid, and phosphate. This is the earliest and most sensitive clinical indicator of chronic cadmium nephrotoxicity, detectable before decline in GFR.
proximal tubule cell link
renal tubular reabsorption link ↓ DECREASED
kidney link
Show evidence (4 references)
PMID:23800513 SUPPORT Human Clinical
"We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome."
Case report confirming cadmium-induced acquired Fanconi syndrome with impaired tubular reabsorption.
PMID:20576581 SUPPORT In Vitro
"Cd reduced the transcriptional expression of megalin and ClC5 and, at the same time, increased the degradation of megalin and ClC5 proteins via the lysosomal pathway in an in vitro model of renal proximal tubular cells."
Demonstrates the molecular mechanism: cadmium downregulates megalin and ClC5, the key receptors for protein reabsorption, explaining Fanconi syndrome.
PMID:32244724 SUPPORT In Vitro
"The exposure of S1 and S2 cells to Cd at 1 and 3 µM for 3 days resulted in significant decreases in the uptakes of β2-MG and metallothionein but not in those of albumin or transferrin."
In vitro study directly demonstrates cadmium impairs endocytic uptake of low-molecular-weight proteins at nonlethal concentrations.
+ 1 more reference
Renal Phosphate Wasting
Impaired proximal tubular phosphate reabsorption leads to chronic phosphaturia and hypophosphataemia. The sustained phosphate loss is the primary metabolic driver of cadmium-induced osteomalacia, as phosphate is essential for hydroxyapatite crystal formation in bone.
phosphate ion transport link ⚠ ABNORMAL
proximal tubule link
Show evidence (1 reference)
PMID:31974582 SUPPORT Human Clinical
"Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
Confirms hypophosphataemia from renal phosphate wasting as the driver of cadmium-induced osteomalacia.
Chronic Kidney Disease Progression
Sustained proximal tubular injury from cadmium accumulation leads to tubulointerstitial inflammation, fibrosis, and progressive nephron loss. Glomerular filtration rate declines as tubulointerstitial nephritis advances, ultimately resulting in chronic kidney disease.
kidney link
Show evidence (2 references)
PMID:39111871 SUPPORT Human Clinical
"She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."
Documents progression to chronic renal failure from sustained cadmium-induced tubular damage.
PMID:20354761 SUPPORT Human Clinical
"Continued and heavy Cd exposure can progress to the clinical renal Fanconi syndrome, and ultimately to renal failure."
Review confirms the progressive nature of cadmium nephrotoxicity from tubular dysfunction to renal failure.
Defective Bone Mineralization
Chronic hypophosphataemia from renal phosphate wasting impairs hydroxyapatite crystal deposition in osteoid, causing osteomalacia. Bone becomes soft and prone to deformation and pathologic fractures. In itai-itai disease, severe demineralization causes fractures from minimal trauma, height loss, and skeletal deformities.
bone mineralization link ↓ DECREASED
bone link
Show evidence (2 references)
PMID:31974582 SUPPORT Human Clinical
"Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
Confirms defective bone mineralization causing osteomalacia in cadmium-exposed workers.
PMID:39111871 SUPPORT Human Clinical
"The shortening of height, bone deformities and fractures, abnormal bone metabolism suggesting osteomalacia, and renal anemia were also noted."
Documents skeletal consequences of defective mineralization in itai-itai disease.
Direct Osteoblast Toxicity
Cadmium directly inhibits osteoblast differentiation and function independently of the renal phosphate wasting pathway. Cadmium disrupts calcium signaling in osteoblasts, inhibits alkaline phosphatase activity, and promotes osteoclast-mediated resorption, contributing to osteoporosis even before significant renal damage develops.
osteoblast link
osteoblast differentiation link ↓ DECREASED
bone link
Show evidence (1 reference)
PMID:18072106 SUPPORT Human Clinical
"We will present a case of cadmium induced peripheral neuropathy, nephropathy, and decreased bone density."
Documents decreased bone density from cadmium exposure, consistent with direct bone cell toxicity.
Hepatic Glutathione Depletion
Cadmium depletes hepatic glutathione stores and inhibits antioxidant enzymes (SOD, GSH-Px, CAT), disrupting the cellular redox balance. Lipid peroxidation increases (elevated MDA), and the glutathione metabolic pathway is overwhelmed. Cadmium also affects drug metabolism through altered cytochrome P450 activity.
hepatocyte link
glutathione metabolic process link ⚠ ABNORMAL
liver link
Show evidence (3 references)
PMID:39381600 SUPPORT Model Organism
"liver SOD, GSH-Px, T-AOC and CAT levels were decreased, and MDA level was increased in Cd-treated goats, and 630 DEPs (up 326, down 304) in the livers of Cd-treated goats."
Proteomic study in goats confirms cadmium-induced hepatic antioxidant depletion.
PMID:40164036 SUPPORT Model Organism
"exercise significantly decreased blood ALT and AST levels, alleviating oxidative stress in the liver by reducing MDA synthesis and enhancing SOD and GSH-PX activities."
Mouse model demonstrates cadmium-induced hepatic oxidative stress with depleted antioxidant enzymes.
PMID:41188353 SUPPORT Model Organism
"Cd exposure altered hepatic lipid homeostasis via the perturbation of steatosis gene expression and lipid species abundances. Additionally, Cd exposure triggered a hepatic antioxidant response"
Mouse model demonstrates cadmium triggers hepatic antioxidant response and disrupts lipid homeostasis, consistent with oxidative stress-driven liver injury.
Hepatocyte Apoptosis
Sustained oxidative stress from glutathione depletion triggers hepatocyte apoptosis via mitochondrial pathways. Cadmium causes release of pro- apoptotic proteins (cytochrome c, caspase-3, Bax) and nuclear damage, leading to progressive hepatocellular loss and liver injury.
hepatocyte link
apoptotic process link ↑ INCREASED
liver link
Show evidence (1 reference)
PMID:40164036 SUPPORT Model Organism
"Exercise inhibited nuclear damage and hepatocyte apoptosis caused by Cd by increasing Bcl-2 protein expression and preventing the release of pro-apoptotic proteins such as caspase-3, Cytc, Bax, caspase-8and cleaved-caspase-3."
Mouse model demonstrates cadmium-induced hepatocyte apoptosis via pro-apoptotic protein release.
NF-kB/MAPK Inflammatory Signaling
Cadmium activates pro-inflammatory signaling cascades including the NF-kB and MAPK/JNK pathways, leading to increased secretion of pro-inflammatory cytokines (IL-1beta, IL-6, TNF-alpha, IL-8, CCL2) and upregulation of COX-2. This chronic inflammatory state exacerbates organ-specific injury in kidney, liver, and intestine.
inflammatory response link ↑ INCREASED
Show evidence (2 references)
PMID:40191670 SUPPORT In Vitro
"the environmental pollutant cadmium is known to increase the secretion of pro-inflammatory cytokines, including interleukin (IL)-6, IL-8, and chemokine (C-C motif) ligand 2 (CCL2) by activating the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways."
In vitro study demonstrates cadmium activation of MAPK and NF-kB inflammatory pathways with cytokine secretion.
PMID:40164036 SUPPORT Model Organism
"exercise, both before and during Cd exposure, can reduce Cd caused pathological damages in the liver and duodenum of mice, suppressing the expression levels of the IL-1beta, IL-6 and TNF-alpha genes."
Mouse model confirms cadmium-induced expression of pro-inflammatory cytokines IL-1beta, IL-6, and TNF-alpha.
Cadmium-Induced Vascular Cholesterol Dysregulation
Cadmium disrupts cholesterol homeostasis in the vascular wall, promoting atherosclerosis through miRNA-mediated dysregulation of cholesterol uptake (CD36), efflux (ABCA1), and hydrolysis (NCEH1). Cadmium upregulates miR-30d-5p and downregulates miR-504-3p, promoting foam cell formation and intracellular lipid accumulation in macrophages. This pathway links cadmium exposure to increased cardiovascular risk, particularly ischemic stroke.
cholesterol homeostasis link ⚠ ABNORMAL
Show evidence (3 references)
PMID:41297938 SUPPORT Model Organism
"Cd exposure, even at a relatively low dosage (4 mg/L), significantly facilitates the progression of atherosclerosis in apolipoprotein E-deficient mice fed a high-fat diet. This pro-atherogenic effect was accompanied by comprehensive disturbances in systemic and vascular cholesterol homeostasis"
Mouse model demonstrates cadmium promotes atherosclerosis through disruption of systemic and vascular cholesterol homeostasis, even at low doses.
PMID:41297938 SUPPORT Model Organism
"we identified miR-30d-5p and miR-504-3p as novel epigenetic regulators mediating Cd-induced foam cell formation. Specifically, Cd treatment upregulated miR-30d-5p and downregulated miR-504-3p, which directly targeted NCEH1 and CD36, respectively, thereby promoting intracellular lipid accumulation."
Identifies the molecular mechanism: cadmium modulates specific miRNAs that regulate cholesterol handling genes, driving foam cell formation and atherosclerotic plaque development.
PMID:41297938 SUPPORT Human Clinical
"plasma miR-30d-5p levels were positively associated with Cd exposure and partially mediated the Cd-stroke association, accounting for 16.4% of the total effect."
Human case-control study (494 ischemic stroke patients vs 494 controls) validates miR-30d-5p as a mediator of cadmium-induced stroke risk.
Acute Pulmonary Injury
Inhalation of cadmium fumes causes acute chemical pneumonitis with diffuse alveolar damage, pulmonary edema, and potentially fatal respiratory failure. Cadmium oxide fumes are particularly hazardous, causing delayed-onset (12-36 hours) acute lung injury that may progress to ARDS.
type II pneumocyte link
inflammatory response link ↑ INCREASED
lung link
Show evidence (2 references)
PMID:16933734 SUPPORT Human Clinical
"Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
Case report of acute lung injury from cadmium fume inhalation.
PMID:22349354 SUPPORT Human Clinical
"In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
Fatal cadmium poisoning cases with pulmonary involvement among multi-organ damage.
✶

Histopathology

5
Diffuse Alveolar Damage
In acute cadmium inhalation, the lungs show diffuse alveolar damage with hyaline membrane formation, alveolar edema, and type II pneumocyte hyperplasia. This is the histopathological correlate of the acute respiratory distress syndrome seen clinically.
Show evidence (2 references)
PMID:22349354 SUPPORT Human Clinical
"In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
Autopsy of two fatal cadmium poisoning cases confirmed lung involvement as part of multi-organ pathological damage.
PMID:16933734 SUPPORT Human Clinical
"Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
Case report of fatal cadmium inhalation with acute lung injury, the clinical manifestation of diffuse alveolar damage.
Renal Tubulointerstitial Disease and Fibrosis
The kidneys show proximal tubular cell necrosis with loss of brush border, tubulointerstitial inflammatory infiltrates, and progressive fibrosis. Cadmium accumulates in the renal cortex. Both cadmium and lead nephropathies are characterized by tubulointerstitial disease and fibrosis, though only early lead nephropathy shows nuclear inclusion bodies.
Show evidence (2 references)
PMID:22349354 SUPPORT Human Clinical
"In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
Autopsy findings confirm kidney as a major target organ in fatal cadmium poisoning.
PMID:19106433 SUPPORT Human Clinical
"both entities are characterized by tubulointerstitial disease and fibrosis, but only early lead nephropathy is characterized by the presence of proximal tubule nuclear inclusion bodies, due to the combination of lead with a lead binding-protein."
Review confirms tubulointerstitial disease and fibrosis as the characteristic renal histopathology of cadmium nephropathy, and distinguishes it from lead nephropathy by the absence of nuclear inclusion bodies.
Hepatocellular Degeneration
Liver pathology shows hepatocellular degeneration and necrosis with gross cadmium excess on tissue analysis. Cadmium accumulates in hepatocytes where it is initially bound to metallothionein; when this binding capacity is overwhelmed, free cadmium causes oxidative damage and cell death.
Show evidence (3 references)
PMID:22349354 SUPPORT Human Clinical
"In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
Autopsy confirmed liver involvement as part of multi-organ cadmium damage.
PMID:7426480 SUPPORT Human Clinical
"Examination of the liver both in life and after death showed a gross excess of cadmium. This was also found in the kidneys after death."
Liver biopsy and postmortem analysis confirmed gross cadmium accumulation in hepatic tissue.
PMID:41412331 SUPPORT Human Clinical
"Cadmium exposure affects liver health by inhibiting steatosis and promoting fibrosis, with renal and lipid metabolism factors acting as mediators, and diet influencing the outcomes."
NHANES cross-sectional study in adolescents demonstrates cadmium exposure promotes hepatic fibrosis, providing human epidemiological evidence for cadmium-induced hepatocellular damage.
Osteomalacic Bone Changes
Bone biopsy shows widened osteoid seams with defective mineralization, consistent with osteomalacia. In severe cases (itai-itai disease), vertebral bodies show structural changes from gross deformity. Bone biopsies are essential for confirming the diagnosis of osteomalacia in cadmium-exposed patients.
Show evidence (2 references)
PMID:7426480 SUPPORT Human Clinical
"Several bone biopsies and detailed metabolic studies showed typical severe osteomalacia"
Multiple bone biopsies in a cadmium-exposed worker confirmed typical severe osteomalacia on histological examination.
PMID:7426480 SUPPORT Human Clinical
"Previously unreported changes were present in the bones, especially the lumbar vertebrae which were probably more the result of gross bone deformity than cadmium deposition."
Histopathological examination revealed novel structural changes in vertebral bone, attributed to mechanical deformity from osteomalacia rather than direct cadmium deposition.
Intracellular Dense Lysosomal Particles
Transmission electron microscopy reveals a large number of dense lysosomal and phagocytic particles in the cytoplasm near the nucleus. This ultrastructural finding is observed across multiple organs and suggests intracellular cadmium sequestration in lysosomes, with potential genotoxic implications from proximity to the nucleus.
Show evidence (1 reference)
PMID:22349354 SUPPORT Human Clinical
"transmission electron microscopy revealed a large number of dense lysosomal and phagocytic particles in the cytoplasm near the nucleus, indicating the need for a genotoxic study of cadmium."
Ultrastructural finding on TEM showing characteristic perinuclear lysosomal cadmium accumulation, a distinctive histopathological marker of cadmium toxicity.
⬡

Causal Graph

graph LR
    Renal_Proximal_Tubular_Cadmium_Uptake["Renal Proximal Tubular Cadmium Uptake"]
    Hepatocyte_Apoptosis["Hepatocyte Apoptosis"]
    Chronic_Kidney_Disease_Progression["Chronic Kidney Disease Progression"]
    Proximal_Tubular_Cell_Injury["Proximal Tubular Cell Injury"]
    Cadmium_Absorption_and_Systemic_Distribution["Cadmium Absorption and Systemic Distribution"]
    Defective_Bone_Mineralization["Defective Bone Mineralization"]
    Cadmium_Induced_Vascular_Cholesterol_Dysregulation["Cadmium-Induced Vascular Cholesterol Dysregulation"]
    Impaired_Tubular_Reabsorption["Impaired Tubular Reabsorption"]
    Hepatic_Glutathione_Depletion["Hepatic Glutathione Depletion"]
    Renal_Phosphate_Wasting["Renal Phosphate Wasting"]
    Direct_Osteoblast_Toxicity["Direct Osteoblast Toxicity"]
    NF_kB_MAPK_Inflammatory_Signaling["NF-kB/MAPK Inflammatory Signaling"]
    Hepatic_Metallothionein_Binding["Hepatic Metallothionein Binding"]

    Cadmium_Absorption_and_Systemic_Distribution --> Hepatic_Metallothionein_Binding
    Cadmium_Absorption_and_Systemic_Distribution --> NF_kB_MAPK_Inflammatory_Signaling
    Cadmium_Absorption_and_Systemic_Distribution --> Direct_Osteoblast_Toxicity
    Cadmium_Absorption_and_Systemic_Distribution --> Hepatic_Glutathione_Depletion
    Cadmium_Absorption_and_Systemic_Distribution --> Cadmium_Induced_Vascular_Cholesterol_Dysregulation
    Hepatic_Metallothionein_Binding --> Renal_Proximal_Tubular_Cadmium_Uptake
    Renal_Proximal_Tubular_Cadmium_Uptake --> Proximal_Tubular_Cell_Injury
    Proximal_Tubular_Cell_Injury --> Impaired_Tubular_Reabsorption
    Proximal_Tubular_Cell_Injury --> Chronic_Kidney_Disease_Progression
    Impaired_Tubular_Reabsorption --> Renal_Phosphate_Wasting
    Renal_Phosphate_Wasting --> Defective_Bone_Mineralization
    Direct_Osteoblast_Toxicity --> Defective_Bone_Mineralization
    Hepatic_Glutathione_Depletion --> Hepatocyte_Apoptosis
    NF_kB_MAPK_Inflammatory_Signaling --> Proximal_Tubular_Cell_Injury
    NF_kB_MAPK_Inflammatory_Signaling --> Hepatic_Glutathione_Depletion

    style Renal_Proximal_Tubular_Cadmium_Uptake fill:#dbeafe
    style Hepatocyte_Apoptosis fill:#dbeafe
    style Chronic_Kidney_Disease_Progression fill:#dbeafe
    style Proximal_Tubular_Cell_Injury fill:#dbeafe
    style Cadmium_Absorption_and_Systemic_Distribution fill:#dbeafe
    style Defective_Bone_Mineralization fill:#dbeafe
    style Cadmium_Induced_Vascular_Cholesterol_Dysregulation fill:#dbeafe
    style Impaired_Tubular_Reabsorption fill:#dbeafe
    style Hepatic_Glutathione_Depletion fill:#dbeafe
    style Renal_Phosphate_Wasting fill:#dbeafe
    style Direct_Osteoblast_Toxicity fill:#dbeafe
    style NF_kB_MAPK_Inflammatory_Signaling fill:#dbeafe
    style Hepatic_Metallothionein_Binding fill:#dbeafe
●

Phenotypes

9
Genitourinary(3) Metabolism(1) Musculoskeletal(2) Nervous System(1) Respiratory(1) Constitutional(1)
Genitourinary 3
Renal Tubular Dysfunction VERY_FREQUENT Renal tubular dysfunction (HP:0000124)
Show evidence (2 references)
PMID:39111871 SUPPORT Human Clinical
"She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."
Documents renal tubular dysfunction as a key manifestation of chronic cadmium exposure.
PMID:23800513 SUPPORT Human Clinical
"We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome."
Confirms acquired Fanconi syndrome from chronic cadmium toxicity.
Low-Molecular-Weight Proteinuria VERY_FREQUENT Proteinuria (HP:0000093)
Show evidence (2 references)
PMID:20354761 SUPPORT Human Clinical
"An early and sensitive manifestation of chronic Cd renal toxicity, which can be useful in individual and population screening, is impaired reabsorption of low molecular weight proteins (LMWP) (also a receptor-mediated process in the proximal tubule) such as retinol binding protein (RBP). This..."
Review identifies LMW proteinuria as the earliest and most sensitive marker of cadmium nephrotoxicity, suitable for population screening.
PMID:19106433 SUPPORT Human Clinical
"Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function."
Confirms the specific LMW proteins excreted in cadmium nephrotoxicity: beta-2-microglobulin, retinol binding protein, and alpha-1-microglobulin.
Chronic Kidney Disease FREQUENT Chronic kidney disease (HP:0012622)
Show evidence (1 reference)
PMID:39111871 SUPPORT Human Clinical
"She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."
Documents chronic renal failure from cadmium exposure.
Metabolism 1
Hypophosphataemia FREQUENT Hypophosphatemia (HP:0002148)
Show evidence (1 reference)
PMID:31974582 SUPPORT Human Clinical
"Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
Confirms hypophosphataemia as the metabolic derangement underlying cadmium-induced osteomalacia.
Musculoskeletal 2
Osteomalacia FREQUENT Osteomalacia (HP:0002749)
Show evidence (2 references)
PMID:31974582 SUPPORT Human Clinical
"Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
Confirms hypophosphataemic osteomalacia from occupational cadmium exposure.
PMID:39111871 SUPPORT Human Clinical
"The shortening of height, bone deformities and fractures, abnormal bone metabolism suggesting osteomalacia, and renal anemia were also noted."
Documents osteomalacia with bone deformities and fractures in itai-itai disease.
Osteoporosis FREQUENT Osteoporosis (HP:0000939)
Show evidence (2 references)
PMID:23800513 SUPPORT Human Clinical
"We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome."
Case report of severe osteoporosis from chronic cadmium toxicity.
PMID:18072106 SUPPORT Human Clinical
"We will present a case of cadmium induced peripheral neuropathy, nephropathy, and decreased bone density."
Confirms decreased bone density (osteoporosis) from cadmium exposure.
Nervous System 1
Peripheral Neuropathy OCCASIONAL Peripheral neuropathy (HP:0009830)
Show evidence (2 references)
PMID:18072106 SUPPORT Human Clinical
"Cadmium is a neurotoxic and nephrotoxic heavy metal"
Identifies cadmium as a neurotoxic heavy metal causing peripheral neuropathy.
PMID:41453694 SUPPORT Human Clinical
"lead (Pb), cadmium (Cd), and arsenic (As) are pervasive environmental toxicants capable of entering the human body via multiple exposure routes, leading to profound neurotoxic effects."
Review of heavy metal neurotoxicity confirms cadmium produces profound neurotoxic effects through multiple exposure routes.
Respiratory 1
Acute Respiratory Distress Syndrome OCCASIONAL Acute respiratory distress syndrome (HP:0033677)
Primarily in acute inhalation exposure
Show evidence (2 references)
PMID:16933734 SUPPORT Human Clinical
"Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
Confirms cadmium as a cause of acute lung injury from inhalation.
PMID:41000307 SUPPORT Human Clinical
"For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required."
Systematic review confirms severe pulmonary involvement requiring mechanical ventilation.
Constitutional 1
Bone Pain FREQUENT Bone pain (HP:0002653)
Show evidence (2 references)
PMID:19341754 SUPPORT Human Clinical
"a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan."
Historical review identifies severe bone pain as the defining symptom of itai-itai disease, the archetypal chronic cadmium poisoning syndrome.
PMID:7426480 SUPPORT Human Clinical
"during the last 12 years of his life the patient had suffered increasing disability from gross bone disease. Several bone biopsies and detailed metabolic studies showed typical severe osteomalacia"
Case report documents 12 years of progressive bone pain and disability from cadmium-induced osteomalacia in an occupationally exposed worker.
💊

Treatments

5
Chelation Therapy MAXO:0001223
Chelating agents (CaNa2-EDTA, DMSA, DMPS) are used to bind and promote urinary excretion of cadmium. Effectiveness is limited due to cadmium's tight binding to metallothionein and intracellular sequestration. BAL (dimercaprol) is contraindicated as it may increase renal cadmium uptake.
Show evidence (2 references)
PMID:41000307 SUPPORT Human Clinical
"The treatment plan includes the use of chelating agents to reduce cadmium levels in the body and antibiotics to maintain the patient's condition."
Systematic review confirms chelating agents as part of standard cadmium poisoning treatment.
PMID:41453694 PARTIAL Human Clinical
"Conventional chelation therapy, when used long-term, can lead to renal and gastrointestinal diseases."
Review highlights significant limitations of conventional chelation therapy, noting long-term use can itself cause renal and gastrointestinal toxicity.
Phosphate Supplementation MAXO:0000058
Neutral phosphate supplements to correct hypophosphataemia from renal phosphate wasting. Phosphate replacement is essential for treating the underlying metabolic defect driving cadmium-induced osteomalacia and results in significant symptom improvement when combined with calcitriol.
Show evidence (1 reference)
PMID:31974582 SUPPORT Human Clinical
"They were initiated on neutral phosphate and calcitriol. On follow-up, they reported significant reduction in severity of symptoms."
Demonstrates effectiveness of phosphate supplementation (combined with calcitriol) for cadmium-induced osteomalacia.
Vitamin D and Calcium Supplementation MAXO:0000110
Calcitriol (active vitamin D) supplementation to treat osteomalacia, bypassing the impaired renal 1-alpha-hydroxylation caused by cadmium nephrotoxicity. Calcium supplementation may also be required to address secondary hyperparathyroidism and calcium malabsorption.
Show evidence (3 references)
PMID:31974582 SUPPORT Human Clinical
"They were initiated on neutral phosphate and calcitriol. On follow-up, they reported significant reduction in severity of symptoms."
Demonstrates effectiveness of calcitriol for cadmium-induced osteomalacia.
PMID:41000307 SUPPORT Human Clinical
"for patients with osteochondropathy, supplementation with calcium and vitamin D is recommended."
Systematic review recommends calcium and vitamin D supplementation for skeletal complications.
PMID:7426480 SUPPORT Human Clinical
"typical severe osteomalacia, which responded well initially to calcium and vitamin D treatment."
Case report confirms initial good response to calcium and vitamin D in cadmium-induced osteomalacia.
Supportive ICU Care MAXO:0000950
For acute cadmium inhalation with pulmonary involvement, intensive care including mechanical ventilation for ARDS and continuous renal replacement therapy (CRRT) for concurrent renal failure may be required.
Show evidence (1 reference)
PMID:41000307 SUPPORT Human Clinical
"For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required."
Systematic review confirms need for ICU-level care in severe acute cadmium poisoning.
Exposure Cessation and Prevention
Removal from cadmium exposure source is essential. Occupational hygiene measures include adequate ventilation, personal protective equipment, and workplace monitoring. Public health interventions include environmental remediation of contaminated soil and water, and regulatory limits on cadmium in food and consumer products.
Show evidence (2 references)
PMID:23800513 SUPPORT Human Clinical
"Therefore, an early diagnosis and prevention of further exposure are important."
Emphasizes the importance of preventing further cadmium exposure given lack of effective treatment.
PMID:31974582 SUPPORT Human Clinical
"regulatory agencies and policy makers ought to survey the silver industry and ensure that the metals used are within permissible safe limits of exposure."
Calls for occupational regulation to prevent cadmium exposure in the silver industry.
🌍

Environmental Factors

4
Occupational Cadmium Exposure
Occupational exposure occurs in silver jewelry manufacturing, zinc smelting, battery production, cadmium plating, welding of cadmium-containing alloys, and pigment manufacturing. Workers inhale cadmium fumes and dust, with the silver cottage industry in developing countries being particularly hazardous due to lack of protective measures.
Show evidence (3 references)
PMID:18072106 SUPPORT Human Clinical
"Silver is mixed with cadmium and then used to make silver jewelry. During this process there is a formation of cadmium fumes, and the workers inhale the fumes."
Describes the mechanism of occupational cadmium exposure in the silver jewelry industry.
PMID:31974582 SUPPORT Human Clinical
"We highlight the occurrence of hypophosphataemic osteomalacia due to chronic cadmium exposure in the silver industry in India."
Confirms the silver industry as a source of chronic cadmium exposure.
PMID:41000307 SUPPORT Human Clinical
"cadmium poisoning primarily affects adult males and is often associated with occupational exposure."
Systematic review confirms occupational exposure as the primary route of cadmium poisoning.
Environmental Cadmium Contamination
Environmental exposure through contaminated food (rice, vegetables grown in cadmium-polluted soil), drinking water, and ambient air near industrial sources. Mining and smelting operations contaminate local waterways and agricultural land, as in the Jinzu River basin in Japan.
Show evidence (1 reference)
PMID:39111871 SUPPORT Human Clinical
"An elderly female farmer with Cd nephropathy residing in a Cd-polluted area in the northern part of the Akita prefecture was identified through hospital-based screening"
Documents environmental cadmium exposure in an agricultural area with contaminated soil.
Tobacco Smoke Exposure
Tobacco smoke is a significant non-occupational source of cadmium. Tobacco plants accumulate cadmium from soil; a single cigarette may contain 1-2 mcg cadmium. Smokers typically have blood cadmium levels 4-5 times higher than non-smokers.
Show evidence (1 reference)
PMID:41000307 SUPPORT Human Clinical
"Common risk factors include smoking and alcohol consumption."
Systematic review identifies smoking as a common risk factor for cadmium poisoning.
Iron Deficiency as Risk Modifier
Low iron stores increase gastrointestinal cadmium absorption via shared divalent metal transporter 1 (DMT1). Iron-deficient individuals, often women and children, are at higher risk of cadmium accumulation from dietary sources.
Show evidence (1 reference)
PMID:41000307 SUPPORT Human Clinical
"The study also found that low iron stores exacerbate cadmium poisoning."
Systematic review confirms that iron deficiency exacerbates cadmium toxicity.
🔬

Biochemical Markers

5
Blood Cadmium Level (INCREASED)
Show evidence (1 reference)
PMID:41000307 SUPPORT Human Clinical
"Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
Systematic review confirms blood cadmium testing as a key diagnostic tool.
Urinary Cadmium Level (INCREASED)
Show evidence (1 reference)
PMID:19364190 SUPPORT Human Clinical
"Conducting pre-flush testing is also currently the clinician's only means of identifying cadmium toxicity."
Identifies pre-challenge urine testing as the key diagnostic method for cadmium toxicity.
Urinary Beta-2-Microglobulin (INCREASED)
Show evidence (1 reference)
PMID:19106433 SUPPORT Human Clinical
"Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function."
Identifies beta-2-microglobulin excretion as a herald of cadmium nephrotoxicity.
Serum Phosphate (DECREASED)
Show evidence (1 reference)
PMID:31974582 SUPPORT Human Clinical
"Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
Confirms hypophosphataemia as a biochemical finding in cadmium-induced osteomalacia.
Hepatic Transaminases (ALT/AST) (INCREASED)
Show evidence (1 reference)
PMID:40164036 SUPPORT Model Organism
"exercise significantly decreased blood ALT and AST levels, alleviating oxidative stress in the liver by reducing MDA synthesis and enhancing SOD and GSH-PX activities."
Mouse model confirms cadmium-induced elevation of hepatic transaminases.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Cadmium Poisoning:

Lead Poisoning Not Yet Curated MONDO:0018019
Overlapping Features Lead poisoning shares features with cadmium toxicity including renal tubular dysfunction, peripheral neuropathy, and occupational exposure in metalworking industries. However, lead poisoning characteristically produces basophilic stippling of erythrocytes, a lead line on gingiva, wrist/foot drop, and abdominal colic, which are not features of cadmium toxicity.
Distinguishing Features
  • Basophilic stippling of erythrocytes on blood smear
  • Lead line on gingiva (Burton line)
  • Wrist drop and foot drop from motor neuropathy (cadmium causes sensory neuropathy)
  • Abdominal colic (lead colic) is characteristic
  • Elevated blood lead levels rather than blood cadmium
  • Osteomalacia and severe phosphate wasting are not typical of lead poisoning
Show evidence (2 references)
PMID:19106433 SUPPORT Human Clinical
"Cadmium in sufficient cumulative dosage leads to the production of the Fanconi syndrome, a generalized proximal tubular reabsorptive defect thought to be related to inhibition of both ATP production and Na-K-ATPase activity. On the other hand, lead accumulation in the proximal tubule leads to..."
Directly contrasts cadmium vs lead nephrotoxicity, showing both settle in proximal tubule but produce different clinical manifestations.
PMID:19106433 SUPPORT Human Clinical
"Beta2-microglobulinuria is not found in lead nephropathy."
Key distinguishing feature: beta-2-microglobulinuria is a hallmark of cadmium nephrotoxicity but absent in lead nephropathy.
Other Causes of Acquired Fanconi Syndrome Not Yet Curated MONDO:0060779
Overlapping Features Acquired Fanconi syndrome can result from multiple causes beyond cadmium, including medications (tenofovir, ifosfamide, cisplatin, valproic acid), multiple myeloma with light chain deposition, and Wilson disease. The clinical presentation of proximal tubular dysfunction with LMW proteinuria, glucosuria, and aminoaciduria is identical regardless of cause.
Distinguishing Features
  • Medication history (tenofovir, cisplatin, ifosfamide) may explain tubular dysfunction
  • Multiple myeloma presents with monoclonal protein on serum/urine electrophoresis
  • Wilson disease shows low ceruloplasmin, elevated urine copper, and Kayser-Fleischer rings
  • Cadmium toxicity is distinguished by elevated blood/urine cadmium levels and occupational or environmental exposure history
Show evidence (1 reference)
PMID:23800513 SUPPORT Human Clinical
"He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure."
Case illustrates how Fanconi syndrome presentation required occupational history and cadmium testing to distinguish from other causes.
Vitamin D Deficiency Osteomalacia Not Yet Curated MONDO:0100471
Overlapping Features Nutritional vitamin D deficiency causes osteomalacia with bone pain, proximal myopathy, and pathologic fractures that closely mimic cadmium- induced osteomalacia. Both conditions present with low serum phosphate and elevated alkaline phosphatase.
Distinguishing Features
  • Low serum 25-hydroxyvitamin D level (< 20 ng/mL)
  • No renal tubular dysfunction or LMW proteinuria
  • Normal urinary cadmium levels
  • Responds to vitamin D supplementation alone without phosphate replacement
  • No occupational heavy metal exposure history
Show evidence (2 references)
PMID:31974582 SUPPORT Human Clinical
"It is essential to maintain a high index of suspicion in diagnosing this condition. A thorough knowledge of the occupational background of patients, as well as ambient conditions at the workplace is of utmost importance in contemplating the possibility of such rare occurrences."
Emphasizes the need for occupational history to distinguish cadmium-induced osteomalacia from more common nutritional causes.
PMID:7426480 SUPPORT Human Clinical
"The mechanism of development of the severe acquired Fanconi syndrome was thought to be a combination of dietary calcium and vitamin D deficiency and impaired calcium absorption from abnormal vitamin D synthesis, related to the cadmium deposition in the renal tubules"
Demonstrates that cadmium-induced osteomalacia involves impaired renal vitamin D synthesis, making it difficult to distinguish from pure nutritional vitamin D deficiency without cadmium testing.
Metal Fume Fever
Overlapping Features Metal fume fever, typically caused by zinc oxide fume inhalation, presents with flu-like symptoms (fever, myalgias, metallic taste) hours after welding or metalworking. It mimics early acute cadmium inhalation but is self-limiting within 24-48 hours and does not progress to ARDS.
Distinguishing Features
  • Self-limiting course resolving within 24-48 hours
  • Does not progress to ARDS or respiratory failure
  • Typically caused by zinc rather than cadmium fumes
  • No renal or skeletal toxicity
  • Cadmium fume exposure causes delayed-onset (12-36 hours) progressive respiratory failure
Show evidence (1 reference)
PMID:16933734 SUPPORT Human Clinical
"Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
Cadmium fume inhalation causes true acute lung injury, unlike the benign self-limiting course of metal fume fever.
X-linked Hypophosphatemia MONDO:0020720
Overlapping Features X-linked hypophosphatemia (XLH) is an inherited disorder of renal phosphate wasting caused by PHEX gene mutations, leading to excess FGF23 and hypophosphataemic rickets/osteomalacia. It presents with similar phosphate wasting and skeletal findings but occurs from childhood without heavy metal exposure.
Distinguishing Features
  • Childhood onset with rickets, short stature, and bowing of lower limbs
  • Family history consistent with X-linked dominant inheritance
  • Elevated FGF23 levels
  • No LMW proteinuria or generalized Fanconi syndrome
  • Normal cadmium levels
  • No occupational or environmental exposure history
Show evidence (1 reference)
PMID:31974582 SUPPORT Human Clinical
"Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
Adult-onset hypophosphataemic osteomalacia from cadmium exposure contrasts with XLH, which presents in childhood; cadmium-induced phosphate wasting is acquired and accompanied by Fanconi syndrome.
📊

Related Datasets

1
The protease DDI2 regulates NRF1-metallothionein pathway in response to Cadmium toxicity in the liver geo:GSE198150
RNA-seq profiling of liver tissue from liver-specific Ddi2 knockout and wild-type mice, investigating how the protease DDI2 regulates the NRF1-metallothionein pathway in response to cadmium toxicity. Identifies DDI2-mediated metallothionein activation as a protective mechanism against cadmium-induced hepatotoxicity.
mouse BULK RNA SEQ n=4 Illumina HiSeq 2500
liver tissue
Conditions: Ddi2 liver-specific knockout wild-type control
PMID:36248746
2 replicates per condition (WT vs Ddi2-KO). Demonstrates that DDI2 cleaves and activates NRF1 to drive metallothionein expression in response to cadmium, linking proteasome homeostasis to heavy metal detoxification.
🔬

Clinical Trials

4
NCT05908383 PHASE_I COMPLETED
Phase I, randomized, double-blind, single-center, single-dose escalation trial evaluating the safety, tolerability, and pharmacokinetic characteristics of injectable GMDTC (a novel cadmium chelation agent) in healthy subjects. This is the foundational safety study for the GMDTC cadmium chelation program.
Show evidence (1 reference)
clinicaltrials:NCT05908383 SUPPORT Human Clinical
"This trial is a randomized, double-blind, single-center, single-dose escalating Phase I clinical trial designed to evaluate the safety, tolerability, and pharmacokinetic characteristics of injectable GMDTC in healthy subjects"
First-in-human safety trial for GMDTC, a novel chelation agent being developed specifically for cadmium poisoning.
NCT06199349 PHASE_I COMPLETED
Phase Ib trial evaluating the safety, tolerability, and pharmacokinetic characteristics of repeated-dose GMDTC injection in people with excessive cadmium levels. This trial extends the Phase I safety profile from healthy volunteers to the target population of cadmium-exposed individuals across three dose cohorts.
Target Phenotypes: Chronic kidney disease ↗
Show evidence (1 reference)
clinicaltrials:NCT06199349 SUPPORT Human Clinical
"This trial is a randomized, double-blind, single-center, single-dose escalating Phase I clinical trial designed to evaluate the safety, tolerability, and pharmacokinetic characteristics of GMDTC for injection after repeated administration in people with excessive cadmium levels."
First trial of GMDTC chelation directly in cadmium-exposed individuals, establishing repeated-dose safety and pharmacokinetics in the target population.
NCT07057414 PHASE_II RECRUITING
Phase IIa, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of GMDTC injection in subjects with elevated cadmium levels. This is the first controlled efficacy trial of a chelation agent specifically developed for cadmium poisoning.
Target Phenotypes: Chronic kidney disease ↗
Show evidence (1 reference)
clinicaltrials:NCT07057414 SUPPORT Human Clinical
"This is a randomized, double-blind, placebo-controlled, single-center Phase IIa clinical study."
First placebo-controlled efficacy trial for cadmium-specific chelation therapy, representing a significant advance given that no approved treatment exists for cadmium poisoning.
NCT00376987 PHASE_II COMPLETED
Clinical trial evaluating whether dietary zinc supplements can reduce serum cadmium levels in current cigarette smokers. Leverages the known competitive interaction between zinc and cadmium at shared divalent metal transporters (DMT1) to potentially reduce cadmium body burden through a simple dietary intervention.
Target Phenotypes: Proteinuria ↗
Show evidence (1 reference)
clinicaltrials:NCT00376987 SUPPORT Human Clinical
"Zinc supplements may lower cadmium levels in smokers and may help prevent DNA damage."
Evaluates a non-chelation approach to reducing cadmium burden by exploiting zinc-cadmium competition at shared intestinal transporters.
{ }

Source YAML

click to show 
name: Cadmium Poisoning
creation_date: '2026-02-10T22:52:02Z'
updated_date: '2026-02-13T22:51:36Z'
description: >-
  Cadmium poisoning is a toxic condition resulting from acute or chronic exposure
  to cadmium, a heavy metal encountered primarily through occupational sources
  (silver jewelry industry, zinc smelting, battery manufacturing), contaminated
  food and water, and tobacco smoke. Acute inhalation of cadmium fumes causes
  severe pneumonitis and acute lung injury. Chronic exposure leads to progressive
  renal tubular dysfunction (Fanconi syndrome), hypophosphataemic osteomalacia,
  osteoporosis, and peripheral neuropathy. The most severe form of chronic cadmium
  toxicity is itai-itai disease, endemic in cadmium-polluted regions of Japan,
  characterized by severe bone pain, fractures, and renal failure. Cadmium has a
  long biological half-life (10-30 years) and there is no effective antidote;
  management centers on exposure cessation, chelation therapy, and supportive care.
category: Environmental
disease_term:
  preferred_term: cadmium poisoning
  term:
    id: MONDO:0043523
    label: cadmium poisoning
parents:
- heavy metal poisoning
has_subtypes:
- name: Acute Cadmium Poisoning (Inhalation)
  description: >-
    Acute cadmium poisoning from inhalation of cadmium fumes or dust, typically
    occurring in occupational settings (welding, smelting, silver jewelry
    manufacturing). Presents with acute lung injury, chemical pneumonitis,
    pulmonary edema, and potentially fatal respiratory failure. Symptoms may be
    delayed 12-36 hours after exposure.
  evidence:
  - reference: PMID:16933734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
    explanation: "Confirms acute cadmium inhalation as a cause of acute lung injury."
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required."
    explanation: "Systematic review confirms severe acute presentations requiring ventilatory support."
- name: Chronic Cadmium Poisoning (Itai-itai Disease)
  description: >-
    Chronic cadmium toxicity from prolonged low-level exposure via contaminated
    food, water, or occupational sources. Characterized by progressive renal
    tubular dysfunction, Fanconi syndrome, hypophosphataemic osteomalacia,
    osteoporosis, and pathologic fractures. Itai-itai disease represents the
    most severe form, endemic in cadmium-polluted areas of Japan.
  evidence:
  - reference: PMID:39111871
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Itai-itai disease is the most severe case of chronic cadmium (Cd) toxicity, which was endemic in Cd-polluted areas in the Jinzu River basin in Toyama prefecture, Japan."
    explanation: "Describes itai-itai disease as the most severe form of chronic cadmium toxicity."
  - reference: PMID:23800513
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure."
    explanation: "Case report confirming chronic cadmium toxicity from occupational exposure with renal and skeletal manifestations."
pathophysiology:
- name: Cadmium Absorption and Systemic Distribution
  description: >-
    Cadmium enters the body via inhalation of fumes/dust or gastrointestinal
    absorption from contaminated food and water. Inhaled cadmium has 25-50%
    bioavailability; oral absorption is lower (3-8%) but enhanced by iron
    deficiency via shared divalent metal transporter 1 (DMT1). Once absorbed,
    cadmium distributes via the bloodstream bound to albumin and accumulates
    in liver, kidney, and bone with a biological half-life of 10-30 years.
  biological_processes:
  - preferred_term: cellular response to cadmium ion
    term:
      id: GO:0071276
      label: cellular response to cadmium ion
  evidence:
  - reference: PMID:23800513
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cadmium has a long biological half-life and there is no effective treatment for people who are exposed to it."
    explanation: "Confirms cadmium's long biological half-life contributing to progressive systemic accumulation."
  - reference: PMID:22349354
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
    explanation: "Autopsy findings confirm systemic cadmium distribution to multiple organs."
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study also found that low iron stores exacerbate cadmium poisoning."
    explanation: "Confirms that iron deficiency enhances cadmium absorption via shared transport mechanisms."
  - reference: PMID:20204475
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "uptake of free Cd(2+) has been demonstrated for the Fe(2+)/H(+) cotransporter divalent metal transporter 1."
    explanation: "Demonstrates that cadmium enters cells via DMT1, the shared iron transporter explaining iron-deficiency enhanced absorption."
  - reference: PMID:31704329
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this is the first study to reveal cadmium-binding proteins in real human blood plasma, which is extremely critical to our understanding of cadmium transportation and accumulation in human blood."
    explanation: "First identification of cadmium-binding proteins (apolipoprotein A-I) in human plasma, elucidating blood transport mechanisms."
  downstream:
  - target: Hepatic Metallothionein Binding
    description: Absorbed cadmium is transported to the liver for initial processing
  - target: NF-kB/MAPK Inflammatory Signaling
    description: Cadmium ions directly activate inflammatory signaling cascades
  - target: Direct Osteoblast Toxicity
    description: Circulating cadmium has direct toxic effects on bone cells
  - target: Hepatic Glutathione Depletion
    description: Cadmium causes oxidative stress in hepatocytes
  - target: Cadmium-Induced Vascular Cholesterol Dysregulation
    description: Circulating cadmium disrupts vascular cholesterol homeostasis via miRNA modulation
- name: Hepatic Metallothionein Binding
  description: >-
    The liver is the primary site of initial cadmium detoxification.
    Hepatocytes synthesize metallothionein (MT), a cysteine-rich protein that
    binds cadmium with high affinity. The cadmium-metallothionein (Cd-MT)
    complex is slowly released into the bloodstream over time. While MT
    binding initially protects against free cadmium toxicity, the Cd-MT
    complex is filtered at the glomerulus and taken up by renal tubular cells,
    effectively transferring the cadmium burden to the kidney.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: detoxification of inorganic compound
    term:
      id: GO:0061687
      label: detoxification of inorganic compound
  evidence:
  - reference: PMID:25042840
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This half-life is partly as a result of metallothioneins (MTs), metal-binding proteins with a high affinity for Cd."
    explanation: "Confirms metallothionein as the primary cadmium-binding protein responsible for cadmium's long biological half-life."
  - reference: PMID:20354761
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The kidney is the main organ affected by chronic Cd exposure and toxicity. Cd accumulates in the kidney as a result of its preferential uptake by receptor-mediated endocytosis of freely filtered and metallothionein bound Cd (Cd-MT) in the renal proximal tubule."
    explanation: "Review confirms that hepatically-produced Cd-MT is filtered and taken up by the kidney, establishing the liver-to-kidney transfer pathway."
  downstream:
  - target: Renal Proximal Tubular Cadmium Uptake
    description: Cd-MT complex released from liver is filtered by glomerulus and reabsorbed by proximal tubule
- name: Renal Proximal Tubular Cadmium Uptake
  description: >-
    The cadmium-metallothionein (Cd-MT) complex is freely filtered at the
    glomerulus due to its small molecular weight (~7 kDa). Proximal tubular
    epithelial cells reabsorb Cd-MT via receptor-mediated endocytosis through
    the megalin/cubilin receptor complex. Once internalized, Cd-MT is degraded
    in lysosomes, releasing free cadmium ions intracellularly. This mechanism
    explains the kidney's particular vulnerability to cadmium accumulation.
  cell_types:
  - preferred_term: proximal tubule cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  biological_processes:
  - preferred_term: receptor-mediated endocytosis
    term:
      id: GO:0006898
      label: receptor-mediated endocytosis
  evidence:
  - reference: PMID:20204475
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the multiligand endocytic receptors megalin and cubilin take up cadmium-metallothionein complexes via receptor-mediated endocytosis."
    explanation: "Demonstrates that megalin and cubilin receptors mediate the endocytic uptake of Cd-MT complexes in proximal tubule."
  - reference: PMID:34298880
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cd2+ complexed to metallothionein (MT) (CdMT) is taken up through receptor-mediated endocytosis (RME) via the PT receptor megalin:cubilin, which is the predominant pathway for reuptake of filtered proteins in the kidney."
    explanation: "Confirms megalin:cubilin as the predominant receptor for Cd-MT uptake in proximal tubule."
  - reference: PMID:20354761
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cd accumulates in the kidney as a result of its preferential uptake by receptor-mediated endocytosis of freely filtered and metallothionein bound Cd (Cd-MT) in the renal proximal tubule. Internalised Cd-MT is degraded in endosomes and lysosomes, releasing free Cd(2+) into the cytosol"
    explanation: "Review details the full Cd-MT uptake pathway: glomerular filtration, receptor-mediated endocytosis, lysosomal degradation, and free Cd2+ release."
  - reference: PMID:25042840
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The high retention properties of the kidneys reside in proximal tubular cells that possess transport mechanisms for Cd-MT uptake, ultimately leading to more Cd accumulation."
    explanation: "Confirms proximal tubular cells possess specific transport mechanisms for Cd-MT uptake."
  downstream:
  - target: Proximal Tubular Cell Injury
    description: Accumulated free cadmium exceeds intracellular metallothionein binding capacity
- name: Proximal Tubular Cell Injury
  description: >-
    When intracellular cadmium exceeds the metallothionein binding capacity
    of proximal tubular cells (typically at renal cortex concentrations above
    200 mcg/g), free cadmium ions cause oxidative stress, mitochondrial
    dysfunction, and activation of apoptotic pathways. Cadmium displaces
    zinc from zinc-finger proteins and disrupts calcium signaling, leading
    to tubular cell death.
  cell_types:
  - preferred_term: proximal tubule cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:39111871
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."
    explanation: "Documents advanced renal tubular dysfunction resulting from proximal tubular cell injury in chronic cadmium exposure."
  - reference: PMID:20354761
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Internalised Cd-MT is degraded in endosomes and lysosomes, releasing free Cd(2+) into the cytosol, where it can generate reactive oxygen species (ROS) and activate cell death pathways."
    explanation: "Review details the mechanism of tubular cell injury: lysosomal release of free Cd2+ generates ROS and activates apoptosis."
  downstream:
  - target: Impaired Tubular Reabsorption
    description: Tubular cell injury and death cause loss of reabsorptive function
  - target: Chronic Kidney Disease Progression
    description: Sustained tubular injury leads to tubulointerstitial fibrosis
- name: Impaired Tubular Reabsorption
  description: >-
    Injury to proximal tubular cells causes Fanconi syndrome, characterized
    by impaired reabsorption of low-molecular-weight proteins (beta-2-
    microglobulin, retinol-binding protein), glucose, amino acids, uric acid,
    and phosphate. This is the earliest and most sensitive clinical indicator
    of chronic cadmium nephrotoxicity, detectable before decline in GFR.
  cell_types:
  - preferred_term: proximal tubule cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  biological_processes:
  - preferred_term: renal tubular reabsorption
    modifier: DECREASED
    term:
      id: GO:0070295
      label: renal absorption
  evidence:
  - reference: PMID:23800513
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome."
    explanation: "Case report confirming cadmium-induced acquired Fanconi syndrome with impaired tubular reabsorption."
  - reference: PMID:20576581
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cd reduced the transcriptional expression of megalin and ClC5 and, at the same time, increased the degradation of megalin and ClC5 proteins via the lysosomal pathway in an in vitro model of renal proximal tubular cells."
    explanation: "Demonstrates the molecular mechanism: cadmium downregulates megalin and ClC5, the key receptors for protein reabsorption, explaining Fanconi syndrome."
  - reference: PMID:32244724
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The exposure of S1 and S2 cells to Cd at 1 and 3 µM for 3 days resulted in significant decreases in the uptakes of β2-MG and metallothionein but not in those of albumin or transferrin."
    explanation: "In vitro study directly demonstrates cadmium impairs endocytic uptake of low-molecular-weight proteins at nonlethal concentrations."
  - reference: PMID:20354761
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An early and sensitive manifestation of chronic Cd renal toxicity, which can be useful in individual and population screening, is impaired reabsorption of low molecular weight proteins (LMWP)"
    explanation: "Review confirms impaired LMWP reabsorption as the earliest and most sensitive indicator of cadmium nephrotoxicity."
  downstream:
  - target: Renal Phosphate Wasting
    description: Impaired proximal tubular phosphate reabsorption causes phosphaturia
- name: Renal Phosphate Wasting
  description: >-
    Impaired proximal tubular phosphate reabsorption leads to chronic
    phosphaturia and hypophosphataemia. The sustained phosphate loss is the
    primary metabolic driver of cadmium-induced osteomalacia, as phosphate
    is essential for hydroxyapatite crystal formation in bone.
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  biological_processes:
  - preferred_term: phosphate ion transport
    modifier: ABNORMAL
    term:
      id: GO:0006817
      label: phosphate ion transport
  evidence:
  - reference: PMID:31974582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
    explanation: "Confirms hypophosphataemia from renal phosphate wasting as the driver of cadmium-induced osteomalacia."
  downstream:
  - target: Defective Bone Mineralization
    description: Chronic hypophosphataemia impairs hydroxyapatite deposition in bone matrix
- name: Chronic Kidney Disease Progression
  description: >-
    Sustained proximal tubular injury from cadmium accumulation leads to
    tubulointerstitial inflammation, fibrosis, and progressive nephron loss.
    Glomerular filtration rate declines as tubulointerstitial nephritis
    advances, ultimately resulting in chronic kidney disease.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:39111871
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."
    explanation: "Documents progression to chronic renal failure from sustained cadmium-induced tubular damage."
  - reference: PMID:20354761
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Continued and heavy Cd exposure can progress to the clinical renal Fanconi syndrome, and ultimately to renal failure."
    explanation: "Review confirms the progressive nature of cadmium nephrotoxicity from tubular dysfunction to renal failure."
- name: Defective Bone Mineralization
  description: >-
    Chronic hypophosphataemia from renal phosphate wasting impairs
    hydroxyapatite crystal deposition in osteoid, causing osteomalacia.
    Bone becomes soft and prone to deformation and pathologic fractures.
    In itai-itai disease, severe demineralization causes fractures from
    minimal trauma, height loss, and skeletal deformities.
  locations:
  - preferred_term: bone
    term:
      id: UBERON:0002481
      label: bone tissue
  biological_processes:
  - preferred_term: bone mineralization
    modifier: DECREASED
    term:
      id: GO:0030282
      label: bone mineralization
  evidence:
  - reference: PMID:31974582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
    explanation: "Confirms defective bone mineralization causing osteomalacia in cadmium-exposed workers."
  - reference: PMID:39111871
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The shortening of height, bone deformities and fractures, abnormal bone metabolism suggesting osteomalacia, and renal anemia were also noted."
    explanation: "Documents skeletal consequences of defective mineralization in itai-itai disease."
- name: Direct Osteoblast Toxicity
  description: >-
    Cadmium directly inhibits osteoblast differentiation and function
    independently of the renal phosphate wasting pathway. Cadmium disrupts
    calcium signaling in osteoblasts, inhibits alkaline phosphatase activity,
    and promotes osteoclast-mediated resorption, contributing to osteoporosis
    even before significant renal damage develops.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  locations:
  - preferred_term: bone
    term:
      id: UBERON:0002481
      label: bone tissue
  biological_processes:
  - preferred_term: osteoblast differentiation
    modifier: DECREASED
    term:
      id: GO:0001649
      label: osteoblast differentiation
  evidence:
  - reference: PMID:18072106
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We will present a case of cadmium induced peripheral neuropathy, nephropathy, and decreased bone density."
    explanation: "Documents decreased bone density from cadmium exposure, consistent with direct bone cell toxicity."
  downstream:
  - target: Defective Bone Mineralization
    description: Impaired osteoblast function compounds the mineralization defect from phosphate wasting
- name: Hepatic Glutathione Depletion
  description: >-
    Cadmium depletes hepatic glutathione stores and inhibits antioxidant
    enzymes (SOD, GSH-Px, CAT), disrupting the cellular redox balance.
    Lipid peroxidation increases (elevated MDA), and the glutathione
    metabolic pathway is overwhelmed. Cadmium also affects drug metabolism
    through altered cytochrome P450 activity.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: glutathione metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0006749
      label: glutathione metabolic process
  evidence:
  - reference: PMID:39381600
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "liver SOD, GSH-Px, T-AOC and CAT levels were decreased, and MDA level was increased in Cd-treated goats, and 630 DEPs (up 326, down 304) in the livers of Cd-treated goats."
    explanation: "Proteomic study in goats confirms cadmium-induced hepatic antioxidant depletion."
  - reference: PMID:40164036
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "exercise significantly decreased blood ALT and AST levels, alleviating oxidative stress in the liver by reducing MDA synthesis and enhancing SOD and GSH-PX activities."
    explanation: "Mouse model demonstrates cadmium-induced hepatic oxidative stress with depleted antioxidant enzymes."
  - reference: PMID:41188353
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cd exposure altered hepatic lipid homeostasis via the perturbation of steatosis gene expression and lipid species abundances. Additionally, Cd exposure triggered a hepatic antioxidant response"
    explanation: "Mouse model demonstrates cadmium triggers hepatic antioxidant response and disrupts lipid homeostasis, consistent with oxidative stress-driven liver injury."
  downstream:
  - target: Hepatocyte Apoptosis
    description: Oxidative stress from glutathione depletion triggers apoptotic cell death
- name: Hepatocyte Apoptosis
  description: >-
    Sustained oxidative stress from glutathione depletion triggers hepatocyte
    apoptosis via mitochondrial pathways. Cadmium causes release of pro-
    apoptotic proteins (cytochrome c, caspase-3, Bax) and nuclear damage,
    leading to progressive hepatocellular loss and liver injury.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:40164036
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Exercise inhibited nuclear damage and hepatocyte apoptosis caused by Cd by increasing Bcl-2 protein expression and preventing the release of pro-apoptotic proteins such as caspase-3, Cytc, Bax, caspase-8and cleaved-caspase-3."
    explanation: "Mouse model demonstrates cadmium-induced hepatocyte apoptosis via pro-apoptotic protein release."
- name: NF-kB/MAPK Inflammatory Signaling
  description: >-
    Cadmium activates pro-inflammatory signaling cascades including the NF-kB
    and MAPK/JNK pathways, leading to increased secretion of pro-inflammatory
    cytokines (IL-1beta, IL-6, TNF-alpha, IL-8, CCL2) and upregulation of
    COX-2. This chronic inflammatory state exacerbates organ-specific injury
    in kidney, liver, and intestine.
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:40191670
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the environmental pollutant cadmium is known to increase the secretion of pro-inflammatory cytokines, including interleukin (IL)-6, IL-8, and chemokine (C-C motif) ligand 2 (CCL2) by activating the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways."
    explanation: "In vitro study demonstrates cadmium activation of MAPK and NF-kB inflammatory pathways with cytokine secretion."
  - reference: PMID:40164036
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "exercise, both before and during Cd exposure, can reduce Cd caused pathological damages in the liver and duodenum of mice, suppressing the expression levels of the IL-1beta, IL-6 and TNF-alpha genes."
    explanation: "Mouse model confirms cadmium-induced expression of pro-inflammatory cytokines IL-1beta, IL-6, and TNF-alpha."
  downstream:
  - target: Proximal Tubular Cell Injury
    description: Inflammatory cytokines exacerbate tubular cell damage
  - target: Hepatic Glutathione Depletion
    description: Inflammatory mediators compound hepatic oxidative stress
- name: Cadmium-Induced Vascular Cholesterol Dysregulation
  description: >-
    Cadmium disrupts cholesterol homeostasis in the vascular wall, promoting
    atherosclerosis through miRNA-mediated dysregulation of cholesterol uptake
    (CD36), efflux (ABCA1), and hydrolysis (NCEH1). Cadmium upregulates
    miR-30d-5p and downregulates miR-504-3p, promoting foam cell formation
    and intracellular lipid accumulation in macrophages. This pathway links
    cadmium exposure to increased cardiovascular risk, particularly ischemic
    stroke.
  biological_processes:
  - preferred_term: cholesterol homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0042632
      label: cholesterol homeostasis
  evidence:
  - reference: PMID:41297938
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cd exposure, even at a relatively low dosage (4 mg/L), significantly facilitates the progression of atherosclerosis in apolipoprotein E-deficient mice fed a high-fat diet. This pro-atherogenic effect was accompanied by comprehensive disturbances in systemic and vascular cholesterol homeostasis"
    explanation: "Mouse model demonstrates cadmium promotes atherosclerosis through disruption of systemic and vascular cholesterol homeostasis, even at low doses."
  - reference: PMID:41297938
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we identified miR-30d-5p and miR-504-3p as novel epigenetic regulators mediating Cd-induced foam cell formation. Specifically, Cd treatment upregulated miR-30d-5p and downregulated miR-504-3p, which directly targeted NCEH1 and CD36, respectively, thereby promoting intracellular lipid accumulation."
    explanation: "Identifies the molecular mechanism: cadmium modulates specific miRNAs that regulate cholesterol handling genes, driving foam cell formation and atherosclerotic plaque development."
  - reference: PMID:41297938
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "plasma miR-30d-5p levels were positively associated with Cd exposure and partially mediated the Cd-stroke association, accounting for 16.4% of the total effect."
    explanation: "Human case-control study (494 ischemic stroke patients vs 494 controls) validates miR-30d-5p as a mediator of cadmium-induced stroke risk."
- name: Acute Pulmonary Injury
  description: >-
    Inhalation of cadmium fumes causes acute chemical pneumonitis with diffuse
    alveolar damage, pulmonary edema, and potentially fatal respiratory failure.
    Cadmium oxide fumes are particularly hazardous, causing delayed-onset (12-36
    hours) acute lung injury that may progress to ARDS.
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:16933734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
    explanation: "Case report of acute lung injury from cadmium fume inhalation."
  - reference: PMID:22349354
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
    explanation: "Fatal cadmium poisoning cases with pulmonary involvement among multi-organ damage."
phenotypes:
- category: Renal
  name: Renal Tubular Dysfunction
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Proximal renal tubular dysfunction manifesting as Fanconi syndrome with
    low-molecular-weight proteinuria (beta-2-microglobulinuria), glucosuria,
    aminoaciduria, and phosphaturia. The earliest and most sensitive indicator
    of chronic cadmium nephrotoxicity.
  evidence:
  - reference: PMID:39111871
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."
    explanation: "Documents renal tubular dysfunction as a key manifestation of chronic cadmium exposure."
  - reference: PMID:23800513
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome."
    explanation: "Confirms acquired Fanconi syndrome from chronic cadmium toxicity."
  phenotype_term:
    preferred_term: Renal tubular dysfunction
    term:
      id: HP:0000124
      label: Renal tubular dysfunction
- category: Renal
  name: Low-Molecular-Weight Proteinuria
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Increased urinary excretion of low-molecular-weight proteins (beta-2-
    microglobulin, retinol-binding protein, alpha-1-microglobulin) reflecting
    impaired proximal tubular reabsorption. A hallmark biomarker of cadmium
    nephrotoxicity used for screening in exposed populations.
  evidence:
  - reference: PMID:20354761
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An early and sensitive manifestation of chronic Cd renal toxicity, which can be useful in individual and population screening, is impaired reabsorption of low molecular weight proteins (LMWP) (also a receptor-mediated process in the proximal tubule) such as retinol binding protein (RBP). This so-called 'tubular proteinuria' is a good index of proximal tubular damage"
    explanation: "Review identifies LMW proteinuria as the earliest and most sensitive marker of cadmium nephrotoxicity, suitable for population screening."
  - reference: PMID:19106433
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function."
    explanation: "Confirms the specific LMW proteins excreted in cadmium nephrotoxicity: beta-2-microglobulin, retinol binding protein, and alpha-1-microglobulin."
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
- category: Musculoskeletal
  name: Osteomalacia
  frequency: FREQUENT
  description: >-
    Defective bone mineralization caused by cadmium-induced renal phosphate
    wasting, leading to hypophosphataemia. Presents with bone pain, proximal
    muscle weakness, waddling gait, and pathologic fractures.
  evidence:
  - reference: PMID:31974582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
    explanation: "Confirms hypophosphataemic osteomalacia from occupational cadmium exposure."
  - reference: PMID:39111871
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The shortening of height, bone deformities and fractures, abnormal bone metabolism suggesting osteomalacia, and renal anemia were also noted."
    explanation: "Documents osteomalacia with bone deformities and fractures in itai-itai disease."
  phenotype_term:
    preferred_term: Osteomalacia
    term:
      id: HP:0002749
      label: Osteomalacia
- category: Musculoskeletal
  name: Osteoporosis
  frequency: FREQUENT
  description: >-
    Decreased bone mineral density from combined effects of renal phosphate and
    calcium wasting, direct cadmium toxicity to osteoblasts, and secondary
    hyperparathyroidism. Contributes to pathologic fractures, particularly in
    chronic exposure.
  evidence:
  - reference: PMID:23800513
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome."
    explanation: "Case report of severe osteoporosis from chronic cadmium toxicity."
  - reference: PMID:18072106
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We will present a case of cadmium induced peripheral neuropathy, nephropathy, and decreased bone density."
    explanation: "Confirms decreased bone density (osteoporosis) from cadmium exposure."
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
- category: Musculoskeletal
  name: Bone Pain
  frequency: FREQUENT
  description: >-
    Severe bone pain, particularly in the legs, pelvis, and spine. The hallmark
    symptom of itai-itai disease (literally "it hurts, it hurts" disease).
    Results from osteomalacia and pathologic fractures.
  evidence:
  - reference: PMID:19341754
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan."
    explanation: "Historical review identifies severe bone pain as the defining symptom of itai-itai disease, the archetypal chronic cadmium poisoning syndrome."
  - reference: PMID:7426480
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "during the last 12 years of his life the patient had suffered increasing disability from gross bone disease. Several bone biopsies and detailed metabolic studies showed typical severe osteomalacia"
    explanation: "Case report documents 12 years of progressive bone pain and disability from cadmium-induced osteomalacia in an occupationally exposed worker."
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
- category: Metabolic
  name: Hypophosphataemia
  frequency: FREQUENT
  description: >-
    Low serum phosphate levels resulting from impaired proximal tubular phosphate
    reabsorption. A key driver of cadmium-induced osteomalacia and a diagnostic
    clue when found with renal tubular dysfunction.
  evidence:
  - reference: PMID:31974582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
    explanation: "Confirms hypophosphataemia as the metabolic derangement underlying cadmium-induced osteomalacia."
  phenotype_term:
    preferred_term: Hypophosphatemia
    term:
      id: HP:0002148
      label: Hypophosphatemia
- category: Renal
  name: Chronic Kidney Disease
  frequency: FREQUENT
  description: >-
    Progressive decline in renal function from chronic cadmium accumulation.
    Glomerular filtration rate declines as tubular damage progresses to
    tubulointerstitial nephritis.
  evidence:
  - reference: PMID:39111871
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had chronic renal failure with a high Cd exposure level and advanced renal tubular dysfunction."
    explanation: "Documents chronic renal failure from cadmium exposure."
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
- category: Neurological
  name: Peripheral Neuropathy
  frequency: OCCASIONAL
  description: >-
    Cadmium-induced peripheral neuropathy, reflecting cadmium's neurotoxic
    properties. Reported in occupationally exposed workers in the silver
    jewelry industry.
  evidence:
  - reference: PMID:18072106
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cadmium is a neurotoxic and nephrotoxic heavy metal"
    explanation: "Identifies cadmium as a neurotoxic heavy metal causing peripheral neuropathy."
  - reference: PMID:41453694
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lead (Pb), cadmium (Cd), and arsenic (As) are pervasive environmental toxicants capable of entering the human body via multiple exposure routes, leading to profound neurotoxic effects."
    explanation: "Review of heavy metal neurotoxicity confirms cadmium produces profound neurotoxic effects through multiple exposure routes."
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
- category: Pulmonary
  name: Acute Respiratory Distress Syndrome
  frequency: OCCASIONAL
  notes: Primarily in acute inhalation exposure
  description: >-
    Acute respiratory distress syndrome from cadmium fume inhalation. May be
    fatal and often presents with delayed onset after initial asymptomatic period.
    Requires mechanical ventilation and intensive care support.
  evidence:
  - reference: PMID:16933734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
    explanation: "Confirms cadmium as a cause of acute lung injury from inhalation."
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required."
    explanation: "Systematic review confirms severe pulmonary involvement requiring mechanical ventilation."
  phenotype_term:
    preferred_term: Acute respiratory distress syndrome
    term:
      id: HP:0033677
      label: Acute respiratory distress syndrome
biochemical:
- name: Blood Cadmium Level
  presence: INCREASED
  biomarker_term:
    preferred_term: cadmium(2+)
    term:
      id: CHEBI:48775
      label: cadmium(2+)
  notes: >-
    Blood cadmium levels reflect recent exposure. Normal levels are typically
    below 5 mcg/L. Levels above 50 mcg/L indicate significant toxicity. Blood
    cadmium testing is essential for confirming diagnosis.
  evidence:
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
    explanation: "Systematic review confirms blood cadmium testing as a key diagnostic tool."
- name: Urinary Cadmium Level
  presence: INCREASED
  biomarker_term:
    preferred_term: cadmium(2+)
    term:
      id: CHEBI:48775
      label: cadmium(2+)
  notes: >-
    Urinary cadmium reflects total body burden and chronic exposure. Pre-
    challenge (unstimulated) urine testing is the primary method for identifying
    cadmium toxicity. Post-chelation challenge testing reflects total body
    stores and helps guide treatment.
  evidence:
  - reference: PMID:19364190
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conducting pre-flush testing is also currently the clinician's only means of identifying cadmium toxicity."
    explanation: "Identifies pre-challenge urine testing as the key diagnostic method for cadmium toxicity."
- name: Urinary Beta-2-Microglobulin
  presence: INCREASED
  biomarker_term:
    preferred_term: Beta-2-Microglobulin
    term:
      id: NCIT:C62657
      label: Beta-2-Microglobulin
  notes: >-
    Elevated urinary beta-2-microglobulin is the most sensitive biomarker of
    cadmium-induced proximal tubular damage, reflecting impaired tubular protein
    reabsorption.
  evidence:
  - reference: PMID:19106433
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function."
    explanation: "Identifies beta-2-microglobulin excretion as a herald of cadmium nephrotoxicity."
- name: Serum Phosphate
  presence: DECREASED
  biomarker_term:
    preferred_term: phosphate ion
    term:
      id: CHEBI:35780
      label: phosphate ion
  notes: >-
    Low serum phosphate from renal phosphate wasting, driving osteomalacia.
  evidence:
  - reference: PMID:31974582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
    explanation: "Confirms hypophosphataemia as a biochemical finding in cadmium-induced osteomalacia."
- name: Hepatic Transaminases (ALT/AST)
  presence: INCREASED
  biomarker_term:
    preferred_term: Alanine Aminotransferase
    term:
      id: NCIT:C25293
      label: Alanine Aminotransferase
  notes: >-
    Elevated ALT and AST levels reflecting hepatocellular injury from cadmium
    hepatotoxicity.
  evidence:
  - reference: PMID:40164036
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "exercise significantly decreased blood ALT and AST levels, alleviating oxidative stress in the liver by reducing MDA synthesis and enhancing SOD and GSH-PX activities."
    explanation: "Mouse model confirms cadmium-induced elevation of hepatic transaminases."
diagnosis:
- name: Blood Cadmium Level
  description: >-
    Blood cadmium reflects recent exposure. Normal levels are typically below
    5 mcg/L; levels above 50 mcg/L indicate significant toxicity. Blood
    cadmium is the initial screening test in suspected acute or occupational
    exposure.
  diagnosis_term:
    preferred_term: blood chemistry measurement
    term:
      id: MAXO:0000787
      label: blood chemistry measurement
  evidence:
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
    explanation: "Systematic review confirms blood testing as part of the diagnostic workup."
- name: Urine Cadmium Level
  description: >-
    Urinary cadmium reflects total body burden and chronic exposure. Pre-
    challenge (unstimulated) urine cadmium is the primary method for
    identifying chronic cadmium toxicity. Post-chelation challenge testing
    reflects total body stores and helps guide treatment decisions.
  diagnosis_term:
    preferred_term: urine chemistry measurement
    term:
      id: MAXO:0000789
      label: urine chemistry measurement
  evidence:
  - reference: PMID:19364190
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conducting pre-flush testing is also currently the clinician's only means of identifying cadmium toxicity."
    explanation: "Identifies pre-challenge urine testing as the key diagnostic method for cadmium toxicity."
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
    explanation: "Systematic review confirms urine testing as part of the diagnostic workup."
- name: Skeletal Imaging
  description: >-
    Bone density measurements (DEXA scan) reveal osteoporosis and osteomalacia.
    Skeletal radiographs may show pseudofractures (Looser zones) characteristic
    of osteomalacia. Essential for evaluating the skeletal complications of
    chronic cadmium exposure.
  diagnosis_term:
    preferred_term: radiograph imaging procedure
    term:
      id: MAXO:0000595
      label: radiograph imaging procedure
  evidence:
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
    explanation: "Systematic review confirms bone density measurements and skeletal imaging as part of diagnostic evaluation."
- name: Renal Imaging
  description: >-
    Kidney ultrasound assesses renal parenchymal damage, cortical thinning,
    and structural changes from chronic cadmium nephrotoxicity. Useful for
    monitoring disease progression in chronically exposed individuals.
  diagnosis_term:
    preferred_term: renal ultrasonography
    term:
      id: MAXO:0010217
      label: renal ultrasonography
  evidence:
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
    explanation: "Systematic review confirms kidney ultrasound as part of the diagnostic workup."
- name: Chest Imaging
  description: >-
    Chest X-ray is important for evaluating acute pulmonary injury from
    cadmium fume inhalation, showing diffuse bilateral infiltrates consistent
    with chemical pneumonitis or ARDS.
  diagnosis_term:
    preferred_term: chest radiograph procedure
    term:
      id: MAXO:0010356
      label: chest radiograph procedure
  evidence:
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnosis relies on a combination of clinical diagnostic tests, blood and urine tests, chest X-rays, kidney ultrasounds, bone density measurements, and skeletal imaging."
    explanation: "Systematic review confirms chest X-ray as part of the diagnostic evaluation."
treatments:
- name: Chelation Therapy
  description: >-
    Chelating agents (CaNa2-EDTA, DMSA, DMPS) are used to bind and promote
    urinary excretion of cadmium. Effectiveness is limited due to cadmium's
    tight binding to metallothionein and intracellular sequestration. BAL
    (dimercaprol) is contraindicated as it may increase renal cadmium uptake.
  treatment_term:
    preferred_term: chelation therapy
    term:
      id: MAXO:0001223
      label: chelator agent therapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: Edetic Acid
        term:
          id: NCIT:C61742
          label: Edetic Acid
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: Succimer
        term:
          id: NCIT:C61953
          label: Succimer
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: 2,3-Dimercapto-1-Propanesulfonic Acid
        term:
          id: NCIT:C87416
          label: 2,3-Dimercapto-1-Propanesulfonic Acid
  evidence:
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The treatment plan includes the use of chelating agents to reduce cadmium levels in the body and antibiotics to maintain the patient's condition."
    explanation: "Systematic review confirms chelating agents as part of standard cadmium poisoning treatment."
  - reference: PMID:41453694
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Conventional chelation therapy, when used long-term, can lead to renal and gastrointestinal diseases."
    explanation: "Review highlights significant limitations of conventional chelation therapy, noting long-term use can itself cause renal and gastrointestinal toxicity."
- name: Phosphate Supplementation
  description: >-
    Neutral phosphate supplements to correct hypophosphataemia from renal
    phosphate wasting. Phosphate replacement is essential for treating the
    underlying metabolic defect driving cadmium-induced osteomalacia and
    results in significant symptom improvement when combined with calcitriol.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    qualifiers:
    - predicate:
        preferred_term: therapeutic agent
        term:
          id: NCIT:C2259
          label: Therapeutic Agent
      value:
        preferred_term: phosphate
        term:
          id: CHEBI:26020
          label: phosphate
  evidence:
  - reference: PMID:31974582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They were initiated on neutral phosphate and calcitriol. On follow-up, they reported significant reduction in severity of symptoms."
    explanation: "Demonstrates effectiveness of phosphate supplementation (combined with calcitriol) for cadmium-induced osteomalacia."
- name: Vitamin D and Calcium Supplementation
  description: >-
    Calcitriol (active vitamin D) supplementation to treat osteomalacia,
    bypassing the impaired renal 1-alpha-hydroxylation caused by cadmium
    nephrotoxicity. Calcium supplementation may also be required to address
    secondary hyperparathyroidism and calcium malabsorption.
  treatment_term:
    preferred_term: vitamin D supplementation
    term:
      id: MAXO:0000110
      label: vitamin D supplementation
  evidence:
  - reference: PMID:31974582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They were initiated on neutral phosphate and calcitriol. On follow-up, they reported significant reduction in severity of symptoms."
    explanation: "Demonstrates effectiveness of calcitriol for cadmium-induced osteomalacia."
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "for patients with osteochondropathy, supplementation with calcium and vitamin D is recommended."
    explanation: "Systematic review recommends calcium and vitamin D supplementation for skeletal complications."
  - reference: PMID:7426480
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "typical severe osteomalacia, which responded well initially to calcium and vitamin D treatment."
    explanation: "Case report confirms initial good response to calcium and vitamin D in cadmium-induced osteomalacia."
- name: Supportive ICU Care
  description: >-
    For acute cadmium inhalation with pulmonary involvement, intensive care
    including mechanical ventilation for ARDS and continuous renal replacement
    therapy (CRRT) for concurrent renal failure may be required.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For patients with concurrent lung and kidney involvement, mechanical ventilation and continuous renal replacement therapy (CRRT) may be required."
    explanation: "Systematic review confirms need for ICU-level care in severe acute cadmium poisoning."
- name: Exposure Cessation and Prevention
  description: >-
    Removal from cadmium exposure source is essential. Occupational hygiene
    measures include adequate ventilation, personal protective equipment, and
    workplace monitoring. Public health interventions include environmental
    remediation of contaminated soil and water, and regulatory limits on
    cadmium in food and consumer products.
  evidence:
  - reference: PMID:23800513
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, an early diagnosis and prevention of further exposure are important."
    explanation: "Emphasizes the importance of preventing further cadmium exposure given lack of effective treatment."
  - reference: PMID:31974582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "regulatory agencies and policy makers ought to survey the silver industry and ensure that the metals used are within permissible safe limits of exposure."
    explanation: "Calls for occupational regulation to prevent cadmium exposure in the silver industry."
environmental:
- name: Occupational Cadmium Exposure
  exposure_term:
    preferred_term: exposure to cadmium
    term:
      id: ECTO:0001566
      label: exposure to cadmium
  description: >-
    Occupational exposure occurs in silver jewelry manufacturing, zinc smelting,
    battery production, cadmium plating, welding of cadmium-containing alloys,
    and pigment manufacturing. Workers inhale cadmium fumes and dust, with the
    silver cottage industry in developing countries being particularly hazardous
    due to lack of protective measures.
  evidence:
  - reference: PMID:18072106
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Silver is mixed with cadmium and then used to make silver jewelry. During this process there is a formation of cadmium fumes, and the workers inhale the fumes."
    explanation: "Describes the mechanism of occupational cadmium exposure in the silver jewelry industry."
  - reference: PMID:31974582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We highlight the occurrence of hypophosphataemic osteomalacia due to chronic cadmium exposure in the silver industry in India."
    explanation: "Confirms the silver industry as a source of chronic cadmium exposure."
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cadmium poisoning primarily affects adult males and is often associated with occupational exposure."
    explanation: "Systematic review confirms occupational exposure as the primary route of cadmium poisoning."
- name: Environmental Cadmium Contamination
  exposure_term:
    preferred_term: exposure to cadmium
    term:
      id: ECTO:0001566
      label: exposure to cadmium
  description: >-
    Environmental exposure through contaminated food (rice, vegetables grown in
    cadmium-polluted soil), drinking water, and ambient air near industrial
    sources. Mining and smelting operations contaminate local waterways and
    agricultural land, as in the Jinzu River basin in Japan.
  evidence:
  - reference: PMID:39111871
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An elderly female farmer with Cd nephropathy residing in a Cd-polluted area in the northern part of the Akita prefecture was identified through hospital-based screening"
    explanation: "Documents environmental cadmium exposure in an agricultural area with contaminated soil."
- name: Tobacco Smoke Exposure
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  description: >-
    Tobacco smoke is a significant non-occupational source of cadmium. Tobacco
    plants accumulate cadmium from soil; a single cigarette may contain 1-2 mcg
    cadmium. Smokers typically have blood cadmium levels 4-5 times higher than
    non-smokers.
  evidence:
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common risk factors include smoking and alcohol consumption."
    explanation: "Systematic review identifies smoking as a common risk factor for cadmium poisoning."
- name: Iron Deficiency as Risk Modifier
  description: >-
    Low iron stores increase gastrointestinal cadmium absorption via shared
    divalent metal transporter 1 (DMT1). Iron-deficient individuals, often
    women and children, are at higher risk of cadmium accumulation from dietary
    sources.
  evidence:
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study also found that low iron stores exacerbate cadmium poisoning."
    explanation: "Systematic review confirms that iron deficiency exacerbates cadmium toxicity."
histopathology:
- name: Diffuse Alveolar Damage
  description: >-
    In acute cadmium inhalation, the lungs show diffuse alveolar damage with
    hyaline membrane formation, alveolar edema, and type II pneumocyte
    hyperplasia. This is the histopathological correlate of the acute
    respiratory distress syndrome seen clinically.
  context: Acute cadmium inhalation
  finding_term:
    preferred_term: Widespread Alveolar Pneumocyte Damage
    term:
      id: NCIT:C96237
      label: Widespread Alveolar Pneumocyte Damage Present
  evidence:
  - reference: PMID:22349354
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
    explanation: "Autopsy of two fatal cadmium poisoning cases confirmed lung involvement as part of multi-organ pathological damage."
  - reference: PMID:16933734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
    explanation: "Case report of fatal cadmium inhalation with acute lung injury, the clinical manifestation of diffuse alveolar damage."
- name: Renal Tubulointerstitial Disease and Fibrosis
  description: >-
    The kidneys show proximal tubular cell necrosis with loss of brush border,
    tubulointerstitial inflammatory infiltrates, and progressive fibrosis.
    Cadmium accumulates in the renal cortex. Both cadmium and lead
    nephropathies are characterized by tubulointerstitial disease and fibrosis,
    though only early lead nephropathy shows nuclear inclusion bodies.
  finding_term:
    preferred_term: Fibrosis
    term:
      id: NCIT:C3044
      label: Fibrosis
  evidence:
  - reference: PMID:22349354
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
    explanation: "Autopsy findings confirm kidney as a major target organ in fatal cadmium poisoning."
  - reference: PMID:19106433
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "both entities are characterized by tubulointerstitial disease and fibrosis, but only early lead nephropathy is characterized by the presence of proximal tubule nuclear inclusion bodies, due to the combination of lead with a lead binding-protein."
    explanation: "Review confirms tubulointerstitial disease and fibrosis as the characteristic renal histopathology of cadmium nephropathy, and distinguishes it from lead nephropathy by the absence of nuclear inclusion bodies."
- name: Hepatocellular Degeneration
  description: >-
    Liver pathology shows hepatocellular degeneration and necrosis with gross
    cadmium excess on tissue analysis. Cadmium accumulates in hepatocytes
    where it is initially bound to metallothionein; when this binding capacity
    is overwhelmed, free cadmium causes oxidative damage and cell death.
  finding_term:
    preferred_term: Degeneration and Necrosis
    term:
      id: NCIT:C120875
      label: Degeneration and Necrosis
  evidence:
  - reference: PMID:22349354
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both cases, multiple organ damage was observed, involving brain, lung, liver, kidney, red blood cells, and platelets"
    explanation: "Autopsy confirmed liver involvement as part of multi-organ cadmium damage."
  - reference: PMID:7426480
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Examination of the liver both in life and after death showed a gross excess of cadmium. This was also found in the kidneys after death."
    explanation: "Liver biopsy and postmortem analysis confirmed gross cadmium accumulation in hepatic tissue."
  - reference: PMID:41412331
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cadmium exposure affects liver health by inhibiting steatosis and promoting fibrosis, with renal and lipid metabolism factors acting as mediators, and diet influencing the outcomes."
    explanation: "NHANES cross-sectional study in adolescents demonstrates cadmium exposure promotes hepatic fibrosis, providing human epidemiological evidence for cadmium-induced hepatocellular damage."
- name: Osteomalacic Bone Changes
  description: >-
    Bone biopsy shows widened osteoid seams with defective mineralization,
    consistent with osteomalacia. In severe cases (itai-itai disease),
    vertebral bodies show structural changes from gross deformity. Bone
    biopsies are essential for confirming the diagnosis of osteomalacia
    in cadmium-exposed patients.
  evidence:
  - reference: PMID:7426480
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several bone biopsies and detailed metabolic studies showed typical severe osteomalacia"
    explanation: "Multiple bone biopsies in a cadmium-exposed worker confirmed typical severe osteomalacia on histological examination."
  - reference: PMID:7426480
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously unreported changes were present in the bones, especially the lumbar vertebrae which were probably more the result of gross bone deformity than cadmium deposition."
    explanation: "Histopathological examination revealed novel structural changes in vertebral bone, attributed to mechanical deformity from osteomalacia rather than direct cadmium deposition."
- name: Intracellular Dense Lysosomal Particles
  description: >-
    Transmission electron microscopy reveals a large number of dense lysosomal
    and phagocytic particles in the cytoplasm near the nucleus. This
    ultrastructural finding is observed across multiple organs and suggests
    intracellular cadmium sequestration in lysosomes, with potential
    genotoxic implications from proximity to the nucleus.
  evidence:
  - reference: PMID:22349354
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "transmission electron microscopy revealed a large number of dense lysosomal and phagocytic particles in the cytoplasm near the nucleus, indicating the need for a genotoxic study of cadmium."
    explanation: "Ultrastructural finding on TEM showing characteristic perinuclear lysosomal cadmium accumulation, a distinctive histopathological marker of cadmium toxicity."
prevalence:
- subtype: General Population
  population: Global
  notes: >-
    Cadmium poisoning is rare in the general population but occurs in
    occupational settings (silver industry, smelting, battery manufacturing)
    and in regions with environmental contamination. Itai-itai disease is
    endemic in cadmium-polluted areas of Japan. The condition primarily
    affects adult males through occupational exposure.
  evidence:
  - reference: PMID:41000307
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This review emphasizes that cadmium poisoning is rare and complex, with non- specific symptoms and a tendency to cause organ damage."
    explanation: "Systematic review confirms cadmium poisoning is rare overall."
differential_diagnoses:
- name: Lead Poisoning
  description: >-
    Lead poisoning shares features with cadmium toxicity including renal tubular
    dysfunction, peripheral neuropathy, and occupational exposure in metalworking
    industries. However, lead poisoning characteristically produces basophilic
    stippling of erythrocytes, a lead line on gingiva, wrist/foot drop, and
    abdominal colic, which are not features of cadmium toxicity.
  disease_term:
    preferred_term: lead poisoning
    term:
      id: MONDO:0018019
      label: lead poisoning
  distinguishing_features:
  - Basophilic stippling of erythrocytes on blood smear
  - Lead line on gingiva (Burton line)
  - Wrist drop and foot drop from motor neuropathy (cadmium causes sensory neuropathy)
  - Abdominal colic (lead colic) is characteristic
  - Elevated blood lead levels rather than blood cadmium
  - Osteomalacia and severe phosphate wasting are not typical of lead poisoning
  evidence:
  - reference: PMID:19106433
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cadmium in sufficient cumulative dosage leads to the production of the Fanconi syndrome, a generalized proximal tubular reabsorptive defect thought to be related to inhibition of both ATP production and Na-K-ATPase activity. On the other hand, lead accumulation in the proximal tubule leads to hyperuricaemia and gout"
    explanation: "Directly contrasts cadmium vs lead nephrotoxicity, showing both settle in proximal tubule but produce different clinical manifestations."
  - reference: PMID:19106433
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Beta2-microglobulinuria is not found in lead nephropathy."
    explanation: "Key distinguishing feature: beta-2-microglobulinuria is a hallmark of cadmium nephrotoxicity but absent in lead nephropathy."
- name: Other Causes of Acquired Fanconi Syndrome
  description: >-
    Acquired Fanconi syndrome can result from multiple causes beyond cadmium,
    including medications (tenofovir, ifosfamide, cisplatin, valproic acid),
    multiple myeloma with light chain deposition, and Wilson disease. The
    clinical presentation of proximal tubular dysfunction with LMW proteinuria,
    glucosuria, and aminoaciduria is identical regardless of cause.
  disease_term:
    preferred_term: acquired Fanconi syndrome
    term:
      id: MONDO:0060779
      label: acquired Fanconi syndrome
  distinguishing_features:
  - Medication history (tenofovir, cisplatin, ifosfamide) may explain tubular dysfunction
  - Multiple myeloma presents with monoclonal protein on serum/urine electrophoresis
  - Wilson disease shows low ceruloplasmin, elevated urine copper, and Kayser-Fleischer rings
  - Cadmium toxicity is distinguished by elevated blood/urine cadmium levels and occupational or environmental exposure history
  evidence:
  - reference: PMID:23800513
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure."
    explanation: "Case illustrates how Fanconi syndrome presentation required occupational history and cadmium testing to distinguish from other causes."
- name: Vitamin D Deficiency Osteomalacia
  description: >-
    Nutritional vitamin D deficiency causes osteomalacia with bone pain,
    proximal myopathy, and pathologic fractures that closely mimic cadmium-
    induced osteomalacia. Both conditions present with low serum phosphate
    and elevated alkaline phosphatase.
  disease_term:
    preferred_term: vitamin D deficiency
    term:
      id: MONDO:0100471
      label: vitamin D deficiency
  distinguishing_features:
  - Low serum 25-hydroxyvitamin D level (< 20 ng/mL)
  - No renal tubular dysfunction or LMW proteinuria
  - Normal urinary cadmium levels
  - Responds to vitamin D supplementation alone without phosphate replacement
  - No occupational heavy metal exposure history
  evidence:
  - reference: PMID:31974582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is essential to maintain a high index of suspicion in diagnosing this condition. A thorough knowledge of the occupational background of patients, as well as ambient conditions at the workplace is of utmost importance in contemplating the possibility of such rare occurrences."
    explanation: "Emphasizes the need for occupational history to distinguish cadmium-induced osteomalacia from more common nutritional causes."
  - reference: PMID:7426480
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mechanism of development of the severe acquired Fanconi syndrome was thought to be a combination of dietary calcium and vitamin D deficiency and impaired calcium absorption from abnormal vitamin D synthesis, related to the cadmium deposition in the renal tubules"
    explanation: "Demonstrates that cadmium-induced osteomalacia involves impaired renal vitamin D synthesis, making it difficult to distinguish from pure nutritional vitamin D deficiency without cadmium testing."
- name: Metal Fume Fever
  description: >-
    Metal fume fever, typically caused by zinc oxide fume inhalation, presents
    with flu-like symptoms (fever, myalgias, metallic taste) hours after
    welding or metalworking. It mimics early acute cadmium inhalation but
    is self-limiting within 24-48 hours and does not progress to ARDS.
  distinguishing_features:
  - Self-limiting course resolving within 24-48 hours
  - Does not progress to ARDS or respiratory failure
  - Typically caused by zinc rather than cadmium fumes
  - No renal or skeletal toxicity
  - Cadmium fume exposure causes delayed-onset (12-36 hours) progressive respiratory failure
  evidence:
  - reference: PMID:16933734
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heavy metal inhalation is a rare cause of acute lung injury. Among the various heavy metals, cadmium is more commonly known to cause acute lung injury."
    explanation: "Cadmium fume inhalation causes true acute lung injury, unlike the benign self-limiting course of metal fume fever."
- name: X-linked Hypophosphatemia
  description: >-
    X-linked hypophosphatemia (XLH) is an inherited disorder of renal phosphate
    wasting caused by PHEX gene mutations, leading to excess FGF23 and
    hypophosphataemic rickets/osteomalacia. It presents with similar phosphate
    wasting and skeletal findings but occurs from childhood without heavy metal
    exposure.
  disease_term:
    preferred_term: X-linked hypophosphatemic rickets
    term:
      id: MONDO:0020720
      label: X-linked hypophosphatemic rickets
  distinguishing_features:
  - Childhood onset with rickets, short stature, and bowing of lower limbs
  - Family history consistent with X-linked dominant inheritance
  - Elevated FGF23 levels
  - No LMW proteinuria or generalized Fanconi syndrome
  - Normal cadmium levels
  - No occupational or environmental exposure history
  evidence:
  - reference: PMID:31974582
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia."
    explanation: "Adult-onset hypophosphataemic osteomalacia from cadmium exposure contrasts with XLH, which presents in childhood; cadmium-induced phosphate wasting is acquired and accompanied by Fanconi syndrome."
clinical_trials:
- name: NCT05908383
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Phase I, randomized, double-blind, single-center, single-dose escalation
    trial evaluating the safety, tolerability, and pharmacokinetic characteristics
    of injectable GMDTC (a novel cadmium chelation agent) in healthy subjects.
    This is the foundational safety study for the GMDTC cadmium chelation program.
  evidence:
  - reference: clinicaltrials:NCT05908383
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This trial is a randomized, double-blind, single-center, single-dose escalating Phase I clinical trial designed to evaluate the safety, tolerability, and pharmacokinetic characteristics of injectable GMDTC in healthy subjects"
    explanation: "First-in-human safety trial for GMDTC, a novel chelation agent being developed specifically for cadmium poisoning."
- name: NCT06199349
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Phase Ib trial evaluating the safety, tolerability, and pharmacokinetic
    characteristics of repeated-dose GMDTC injection in people with excessive
    cadmium levels. This trial extends the Phase I safety profile from healthy
    volunteers to the target population of cadmium-exposed individuals across
    three dose cohorts.
  target_phenotypes:
  - preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: clinicaltrials:NCT06199349
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This trial is a randomized, double-blind, single-center, single-dose escalating Phase I clinical trial designed to evaluate the safety, tolerability, and pharmacokinetic characteristics of GMDTC for injection after repeated administration in people with excessive cadmium levels."
    explanation: "First trial of GMDTC chelation directly in cadmium-exposed individuals, establishing repeated-dose safety and pharmacokinetics in the target population."
- name: NCT07057414
  phase: PHASE_II
  status: RECRUITING
  description: >-
    Phase IIa, randomized, double-blind, placebo-controlled trial evaluating
    the safety and efficacy of GMDTC injection in subjects with elevated cadmium
    levels. This is the first controlled efficacy trial of a chelation agent
    specifically developed for cadmium poisoning.
  target_phenotypes:
  - preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: clinicaltrials:NCT07057414
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a randomized, double-blind, placebo-controlled, single-center Phase IIa clinical study."
    explanation: "First placebo-controlled efficacy trial for cadmium-specific chelation therapy, representing a significant advance given that no approved treatment exists for cadmium poisoning."
- name: NCT00376987
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Clinical trial evaluating whether dietary zinc supplements can reduce serum
    cadmium levels in current cigarette smokers. Leverages the known competitive
    interaction between zinc and cadmium at shared divalent metal transporters
    (DMT1) to potentially reduce cadmium body burden through a simple dietary
    intervention.
  target_phenotypes:
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: clinicaltrials:NCT00376987
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Zinc supplements may lower cadmium levels in smokers and may help prevent DNA damage."
    explanation: "Evaluates a non-chelation approach to reducing cadmium burden by exploiting zinc-cadmium competition at shared intestinal transporters."
datasets:
- accession: geo:GSE198150
  title: The protease DDI2 regulates NRF1-metallothionein pathway in response to Cadmium toxicity in the liver
  description: >-
    RNA-seq profiling of liver tissue from liver-specific Ddi2 knockout and
    wild-type mice, investigating how the protease DDI2 regulates the
    NRF1-metallothionein pathway in response to cadmium toxicity. Identifies
    DDI2-mediated metallothionein activation as a protective mechanism against
    cadmium-induced hepatotoxicity.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_types:
  - preferred_term: liver tissue
    tissue_term:
      preferred_term: liver
      term:
        id: UBERON:0002107
        label: liver
  sample_count: 4
  conditions:
  - Ddi2 liver-specific knockout
  - wild-type control
  platform: Illumina HiSeq 2500
  publication: PMID:36248746
  notes: >-
    2 replicates per condition (WT vs Ddi2-KO). Demonstrates that DDI2
    cleaves and activates NRF1 to drive metallothionein expression in
    response to cadmium, linking proteasome homeostasis to heavy metal
    detoxification.