STEPTRACKERGASTROINTESTINAL | PATHOLOGY + GENETICS + BIOCHEMISTRY | HIGH-YIELD REVIEW

Inherited & Metabolic Liver Disease

Too much iron, too much copper, a misfolded protein, and the aspirin-triggered mitochondrial crisis in children.

FOCUS ON
Hemochromatosis: HFE, ↓ hepcidin → iron overload; cirrhosis + diabetes + bronze skin, cardiomyopathy; ↑ ferritin and transferrin saturation; phlebotomy. Wilson: ATP7B → copper in liver, brain (putamen), cornea (Kayser-Fleischer); ↓ ceruloplasmin; chelate. α1-antitrypsin: PAS⁺ globules + emphysema. Reye: aspirin + virus in a child.
DISORDER
MECHANISM · GENETICS
FEATURES
CLUE · TREATMENT
Hereditary hemochromatosis
HFE C282Y (AR) → ↓ hepcidin → unchecked ferroportin → ↑ iron absorption; iron → ROS
Men 40s–50s (women later — menstruation); fatigue, arthralgia
↑ ferritin, ↑ transferrin saturation, ↓ TIBC · Prussian blue stain
Hemochromatosis — organs
Iron (hemosiderin) deposits in parenchyma
Cirrhosis → HCC · diabetes (pancreas) · skin bronzing · dilated/restrictive cardiomyopathy · hypogonadism (pituitary) · arthropathy (2nd/3rd MCP, CPPD)
"Bronze diabetes" · phlebotomy; deferoxamine, deferasirox
Iron and infection
Siderophilic organisms thrive
Vibrio vulnificus (raw oysters), Yersinia, Listeria
Also with chelation by deferoxamine
Secondary iron overload
Repeated transfusions (β-thalassemia major, sickle cell), ineffective erythropoiesis
Same organ damage; iron first in macrophages
Chelation (not phlebotomy if anemic)
Wilson disease
ATP7B (chr 13, AR) → copper not excreted into bile or loaded onto ceruloplasmin
Liver: hepatitis, cirrhosis, acute failure · Coombs-negative hemolysis · renal Fanconi
↓ ceruloplasmin, ↑ urine copper, ↑ liver copper
Wilson — brain and eye
Free copper deposits in the basal ganglia (putamen) and Descemet membrane
Parkinsonism, wing-beating tremor, dysarthria, dystonia, psychiatric changes; Kayser-Fleischer rings
Penicillamine, trientine; zinc blocks absorption
α1-antitrypsin deficiency
SERPINA1; PiZZ protein misfolds and is trapped in hepatocyte ER
Liver: PAS⁺, diastase-resistant globules (periportal) → cirrhosis, HCC · lung: panacinar emphysema (lower lobes)
Liver injury = toxic gain · lung injury = loss of function
Reye syndrome
Aspirin during a viral illness (influenza, varicella) in children → mitochondrial injury, ↓ β-oxidation
Vomiting, encephalopathy (cerebral edema), hepatomegaly; microvesicular steatosis; hypoglycemia, ↑ ammonia
Avoid aspirin in children (except Kawasaki)
Glycogen storage disease I
Glucose-6-phosphatase deficiency (von Gierke)
Severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia, ↑ TG
Frequent cornstarch feeds · hepatic adenoma risk
Galactosemia
GALT deficiency → galactitol and galactose-1-P accumulate
Infant: jaundice, hepatomegaly, vomiting, cataracts, failure to thrive
E coli sepsis · remove lactose
Hereditary fructose intolerance
Aldolase B deficiency → fructose-1-P traps phosphate
Hypoglycemia, vomiting, jaundice after fruit, juice or sucrose
Infant starts weaning foods

Mechanism — hepcidin and iron

Normal HFESenses iron
→
HepcidinDegrades ferroportin
→
Less iron absorbed
HFE mutation
→
↓ Hepcidin
→
Ferroportin stays openGut + macrophages
→
Iron overloadFenton reaction → ROS → fibrosis

Iron studies

STATE
FERRITIN
TIBC
% SATURATION
Hemochromatosis
↑↑
↓
↑↑ (> 45%)
Iron deficiency
↓
↑
↓↓
Chronic disease
↑
↓
↓ / normal
Pregnancy / OCP
Normal
↑
↓

How it's tested

COMMON CONFUSIONCeruloplasmin is low in Wilson disease, but total serum copper is often low too. Free (non-ceruloplasmin) copper and urine copper are high.
THE TRAPA young patient with hepatitis plus a movement or psychiatric disorder — or Coombs-negative hemolytic anemia — should be tested for Wilson disease.
YOUR APPROACHLiver disease + extra organ clue (skin, heart, joints, eyes, brain, lungs) + iron or copper studies → gene → treatment.

If you see… think…

Man with diabetes, bronze skin, hepatomegaly, transferrin sat 80% → hemochromatosis
Hemochromatosis patient with sepsis after raw oysters → Vibrio vulnificus
Iron overload in a β-thalassemia patient → transfusional hemosiderosis
Teen with tremor, odd behavior and hepatitis → Wilson disease
Golden-brown ring at the edge of the cornea → Kayser-Fleischer ring
Low ceruloplasmin + high urine copper → Wilson — penicillamine
Young nonsmoker with emphysema and cirrhosis → α1-antitrypsin deficiency
PAS⁺ diastase-resistant hepatocyte globules → α1-antitrypsin (PiZZ)
Child given aspirin for chickenpox, now vomiting and confused → Reye syndrome
Infant with jaundice, cataracts and E coli sepsis → galactosemia