What is the classic triad of Wilson disease?

Liver disease (cirrhosis), neuropsychiatric symptoms (tremor, personality changes), and Kayser-Fleischer rings (copper deposits in Descemet membrane). Caused by ATP7B mutation leading to ceruloplasmin deficiency and free copper accumulation.

What does zinc deficiency cause in clinical practice?

Dysgeusia (altered taste), anosmia, alopecia, delayed wound healing, male hypogonadism, and immune suppression. Acrodermatitis enteropathica is the autosomal recessive form with perioral/perianal/acral dermatitis plus diarrhea plus alopecia.

What does selenium deficiency cause?

Dilated cardiomyopathy (Keshan disease), seen in selenium-depleted soils or long-term total parenteral nutrition without trace mineral supplementation.

What is Menkes disease?

X-linked recessive disorder caused by ATP7A mutation -> defective intestinal copper absorption and transport -> systemic copper deficiency. Presents with steely/kinky hair, hypotonia, seizures, and developmental regression in infancy.

Trace Minerals: Zinc, Copper, Selenium | clinical Deep-Dive

Clinical Findings

Kayser-Fleischer Rings · Wilson Disease

Copper deposits in Descemet membrane of the cornea. Visible as golden-brown rings on slit-lamp exam. Pathognomonic for copper overload.

Kayser-Fleischer ring with arrow indicating copper deposit in cornea

Kayser-Fleischer ring slit-lamp photograph showing golden-brown corneal ring

Kayser-Fleischer ring - close-up view showing copper deposit around iris

Tap any image to enlarge. Photos via Wikimedia Commons.

Section I

🪛 The Minerals

Tap any element to expand its full clinical profile.

20

Ca

Calcium

12

Mg

Magnesium

30

Zn

Zinc

29

Cu

Copper

26

Fe

Iron

What It Does

Intracellular calcium triggers all muscle contraction
Only two membranes depolarize using calcium instead of sodium: atrium and thalamus 🔑A-T for Atrium-Thalamus: the two rebels that depolarize with Ca2+ instead of Na+.
Cardiac ventricle uses calcium-induced calcium releaseSmall amount of extracellular Ca2+ enters through L-type channels during the plateau phase, then triggers massive Ca2+ release from the sarcoplasmic reticulum via ryanodine receptors.
Presynaptic influx required for release of all neurotransmitters
Required for normal bone and teeth development

Clinical Pearl

Babies in utero need calcium for neurotransmitter release -> deficiency can cause developmental delay

What It Does

Cofactor for ALL kinases (why?)Kinases need ATP. Mg2+ stabilizes the negative charges on ATP's phosphate tail so the kinase can work. No Mg = no kinase activity.
Cofactor for PTH -> low Mg can mimic hypoparathyroidism
Cotransporter with K+ in the early distal convoluted tubule

Board Trap

Can't fix hypokalemia until you fix hypomagnesemia -> they share a cotransporter in the DCT. If Mg is low, K+ keeps leaking out no matter how much you replace.

What It Does

Needed by hair, skin, sperm, taste buds, and 100+ enzymes 🔑Zinc = the vanity mineral. Hair, skin, taste, and swimmers. Everything you'd notice on a date.
Forms zinc finger domains in transcription factors -> zinc plays a role in DNA binding
Cofactor for collagenase (remodeling phase of wound healing)

Deficiency

Dysgeusia (altered taste) and anosmia
Alopecia, delayed wound healing, male hypogonadism
Acrodermatitis enteropathica: autosomal recessive, ZIP4/SLC39A4 transporter defect -> can't absorb zinc in jejunum -> perioral + perianal + acral dermatitis + diarrhea + alopecia (triad)

What It Does

Cofactor for lysyl oxidase -> crosslinks collagen and elastin (why it matters)Without copper, lysyl oxidase can't crosslink collagen. Result: connective tissue weakness, friable vessels.
Needed by Complex IV of the electron transport chain (cytochrome c oxidase)

Excess: Wilson Disease

Autosomal recessive mutation in ATP7B gene (chromosome 13) -> can't incorporate copper into ceruloplasmin or excrete it in bile
Free copper deposits in: basal ganglia/lenticular nucleus (tremor, dysarthria), corneal Descemet membrane (Kayser-Fleischer rings), liver (cirrhosis), kidneys (Fanconi syndrome)
Labs: low serum ceruloplasmin + elevated urine copper
Treatment: penicillamine or trientine (copper chelators); oral zinc (blocks absorption); liver transplant for acute failure
Penicillamine side effects: drug-induced lupus; avoid if penicillin anaphylaxis

Deficiency: Menkes Disease

X-linked recessive mutation in ATP7A -> defective copper absorption and transport -> systemic copper deficiency
Results in: defective lysyl oxidase -> brittle "kinky" steely hair, hypotonia, seizures, developmental delay, risk of cerebral aneurysms
Memory: ATP7A = Absent (copper lost) vs ATP7B = Buildup (Wilson's accumulates)

What It Does

Forms heme in hemoglobin and myoglobin
Ferrous iron (Fe2+) binds oxygen -> the functional form
Ferric iron (Fe3+) is oxidized -> cannot bind oxygen 🔑Fe2+ = ferrOUS = useOUS. Fe3+ = ferrIC = useless IC.
Vitamin C keeps iron in Fe2+ state for GI absorption

Hepcidin

Hepcidin is a liver peptide that blocks ferroportin (iron exporter on enterocytes and macrophages)
Iron high -> hepcidin rises -> ferroportin blocked -> iron trapped in enterocytes (shed in stool) and macrophages -> less circulating iron
Anemia of chronic disease: inflammation -> IL-6 -> hepcidin -> iron sequestered in macrophages -> low serum iron BUT high ferritin
Board trap: low serum iron + HIGH ferritin = anemia of chronic disease; low serum iron + low ferritin = true iron deficiency

Section II

🔬 Trace Elements

Tiny amounts, massive consequences. Each has a single board association.

24

Cr

Chromium

34

Se

Selenium

42

Mo

Molybdenum

25

Mn

Manganese

9

F

Fluoride

What It Does

Enhances insulin action -> delays progression of diabetes

Deficiency

Impaired glucose tolerance / diabetes -> seen in clinical practice in long-term TPN without trace minerals 🔑Chromium = Chrome = shiny insulin receptors. No chrome, receptors go dull. Glucose spikes.

What It Does

Essential cofactor for glutathione peroxidase -> antioxidant defense
Needed primarily by the heart

Deficiency: Keshan Disease

Dilated cardiomyopathy -> endemic in selenium-poor soils of rural China; also seen in long-term TPN

Excess

Garlic-smelling breath (arsenic also does this) 🔑Se-lenium and Arsenic: the two garlic-breath cousins. Se-licious.

What It Does (with Manganese)

Needed by enzymes in glycolysis
Both xanthine oxidase needs molybdenum AND manganese (why it matters)Xanthine oxidase converts hypoxanthine to xanthine to uric acid. Allopurinol blocks this enzyme to treat gout.

What It Does

Needed by enzymes in glycolysis
Partners with molybdenum for xanthine oxidase (uric acid production)

What It Does

Needed for teeth and bone development and hardening

Excess / Poisoning

Blocks enolase of glycolysis -> ATP famine (connection!)Enolase converts 2-phosphoglycerate to PEP in glycolysis. Block it and you choke off ATP production. Rapidly dividing cells die first.
X-ray: bright, shiny teeth and bones; horizontal white and dark lines in teeth (dental fluorosis)
Death from heart failure (heart needs constant energy)

From the Attending

The clinical medicine love to disguise Wilson disease. You will see a young patient with either liver disease or psychiatric symptoms or a movement disorder, and you have to connect all three. The trick: any young patient with a movement disorder that looks like Parkinson gets a slit-lamp exam and a ceruloplasmin level before anything else. That's the diagnosis you cannot miss. Hemochromatosis similarly hides in plain sight: bronze skin + diabetes + joint pain in a middle-aged man is the bronze diabetes triad. The HFE mutation, serial phlebotomy as treatment, and the distinction from secondary hemochromatosis (treat with chelation, not phlebotomy) are all high-yield. Know your clues. Every time.

Copper Transport

Copper Metabolism: Normal vs Wilson Disease

Watch copper move through the body. Toggle between normal transport and Wilson disease to see where the pathway breaks.

Copper Pathway: Live Animation

Animated: copper absorption, ceruloplasmin binding, and deposition pattern in disease.

Board Favorite

Wilson Disease vs Huntington Disease

Both cause movement disorders with psychiatric symptoms in a younger patient. The liver and eyes tell you which is which.

Feature	Huntington Disease	Wilson Disease
Inheritance	Autosomal dominant	Autosomal recessive
Genetic cause	CAG trinucleotide repeats -> caudate atrophy	ATP7B mutation -> copper accumulation
Age of onset	30-50s (anticipation)	Before 40 (often 5-35)
Movement	Chorea	Tremor, dysarthria, dystonia
Liver disease?	No	Yes: cirrhosis, liver failure
Eye finding?	None	Kayser-Fleischer rings
Lab finding	None specific	Low ceruloplasmin, high urine copper
Treatment	Dopamine blockers (symptom management)	Penicillamine, trientine, zinc
Most common cause of death	Suicide, aspiration pneumonia	Liver failure

Huntington Disease

InheritanceAutosomal dominant

Genetic causeCAG repeats → caudate atrophy

Age of onset30-50s (anticipation)

MovementChorea

Liver diseaseNo

Eye findingNone

Lab

Treatment

Death

Wilson Disease

InheritanceAutosomal recessive

Genetic causeATP7B mutation → copper buildup

Age of onsetBefore 40 (often 5-35)

MovementTremor, dysarthria, dystonia

Liver diseaseYes: cirrhosis, liver failure

Eye findingKayser-Fleischer rings

Lab

Treatment

Death

💡 ATP7A vs ATP7B

ATP7A defect = Menkes disease = copper Absent from body (X-linked recessive, infant onset).
ATP7B defect = Wilson disease = copper Builds up in tissues (autosomal recessive, young adult onset).

Challenge

Which Deficiency?

Work through the clinical clues one step at a time before seeing the answer.

🎯 Clinical Identification Challenge

An infant is brought in for brittle, depigmented, coarse hair and new seizures. Serum copper is 36 mcg/dL (70-140 mcg/dL). Which deficiency is causing this presentation?

Test Yourself

🎮 Match the Mineral

Drag each mineral to its signature finding. Tap to select and tap the target on mobile.

Mineral

Signature Finding

Board Walkthrough

🎯 3rd-Order Vignettes

Six original clinical vignettes. One at a time. Answer, then read the explanation. The teaching chain drops after each one.

VIGNETTE 1 OF 6