Metabolic and inherited liver diseases

1. Non-Inherited Metabolic Liver Disease — NAFLD / NASH

Definition

• NAFLD = fatty liver + liver disease in people who do not drink alcohol.
• Spectrum: simple steatosis → NASH (non-alcoholic steatohepatitis) → fibrosis/cirrhosis.
• NASH mimics alcoholic hepatitis: hepatocyte destruction, parenchymal inflammation, pericellular fibrosis.

Associations (metabolic syndrome)

• Insulin resistance, T2DM, obesity, dyslipidemia (↑ TAG, ↓ HDL, ↑ LDL).

Pathogenesis

• Insulin resistance → TAG accumulation in hepatocytes → lipid peroxidation → mitochondrial / membrane damage → apoptosis.

Clinical

• Steatosis usually asymptomatic.
• NASH/advanced: fatigue, RUQ discomfort, weakness.
• Slow progression; liver biopsy for definitive Dx.
• Tx: weight loss + improve insulin sensitivity.

2. Inherited Metabolic Liver Diseases

A) Hemochromatosis — “bronze diabetes”

• Genetic disorder of excessive iron accumulation.
• Normal body iron 2–6 g → hemochromatosis ~50 g.
• Name explained:
  1. Bronze skin = hemosiderin + ↑ melanin
  2. Diabetes = pancreatic damage

Pathogenesis

• Mutation in HFE gene → dysregulated hepcidin (hepatic iron hormone normally blocks intestinal Fe absorption).
• ↓ Hepcidin → uncontrolled intestinal iron absorption → macrophage saturation → free iron leaks into tissues → ROS / peroxidation → necrosis + fibrosis.

Morphology

• Hemosiderin deposition: liver, pancreas, myocardium, skin, adrenals.
• Liver cirrhosis; pancreatic fibrosis (→ bronze diabetes).

Clinical

• Almost exclusively males (♀ protected by menstruation).
• Onset 5th decade.
• Sx: hepatomegaly, abdominal pain, skin pigmentation, diabetes, cardiac dysfunction (cardiomyopathy/arrhythmia).
• Death: HCC, cirrhosis, cardiac disease.
• Tx: regular phlebotomy (blood withdrawal).

B) Wilson’s Disease

• AR disorder of copper metabolism → toxic Cu accumulation in liver, eye, brain.

Pathogenesis

• Cu absorption + transport to liver normal.
• Defective canalicular Cu excretion (mutation in ATP7B) → failure to incorporate into ceruloplasmin / excrete in bile → progressive Cu accumulation → toxic injury.

Morphology

• Liver: fatty change, hepatitis, cirrhosis.
• Brain: basal ganglia atrophy / cavitation.
• Eye: Kayser-Fleischer rings (Cu in Descemet membrane at corneal limbus).

Clinical

• Rarely manifests before age 6.
• Liver disease OR neuropsychiatric Sx (behavioral changes, psychosis, Parkinsonism-like).
• Biochemistry: ↓ serum ceruloplasmin, ↑ hepatic Cu, ↑ urinary Cu.

C) α1-Antitrypsin Deficiency (AAT / A1AT)

• AR disorder → abnormally low serum AAT.
• AAT normally inhibits proteases (esp. neutrophil elastase at inflammation sites).
• Hepatocyte fails to secrete AAT → protein accumulates intracellularly (PAS-positive globules) → hepatic injury.
• Pulmonary emphysema (panacinar) because unchecked elastase digests lung tissue.
• Liver damage variable: cirrhosis, fulminant failure, or minor abnormalities.
• Tx: liver transplantation if severe; no lung-specific cure.

3. Quick Comparison

Disease	Gene / metal	Liver	Other sites	Eye / skin	Tx
Hemochromatosis	HFE, iron	Cirrhosis, HCC	Pancreas (DM), heart, joints	Bronze skin	Phlebotomy
Wilson	ATP7B, copper	Hepatitis → cirrhosis	Basal ganglia (Parkinsonism, psych)	Kayser-Fleischer ring	Chelation (penicillamine)
α1-AT def.	SERPINA1	Variable (cirrhosis to FLF)	Panacinar emphysema	—	Transplant

💡 High-yield: NAFLD/NASH = obesity / T2DM / metabolic syndrome — #1 chronic liver dz in west. Hemochromatosis = HFE, ↓ hepcidin, iron overload → “bronze diabetes” + cardiomyopathy + HCC; Tx phlebotomy. Wilson = ATP7B (AR), ↓ ceruloplasmin, Kayser-Fleischer ring, basal ganglia / Parkinsonism. α1-AT def. = liver (PAS-positive globules) + panacinar emphysema.