II-3. Liver dysfunction (1)

肝機能障害（1）

Liver Functions

Intermediary metabolism: carbohydrate (glycemic control, gluconeogenesis/glycolysis), lipid (VLDL production), protein (albumin, coagulation factors, acute-phase proteins).
Endo-/xenobiotic metabolism: inactivation (bilirubin, ammonia, steroid hormones) / activation (vitamin D); drug biotransformation (phase I, II).
Endocrine: hormone precursors (vitamin D), growth factors (IGF-1/2), hepcidin.
Excretion: bile. Storage: glycogen, vitamin A, metals.

Causes of Liver & Biliary Disease

Metabolic (accumulation, chronic): NAFLD (obesity/T2DM → lipids), hemochromatosis (iron), Wilson’s (copper, AR), α1-antitrypsin deficiency (protein, AR) → fibrosis/cirrhosis/HCC.
Infective: HAV (acute, benign), HBV/HCV (chronic → cirrhosis, HCC).
Toxic/drug: alcoholic liver injury (chronic), paracetamol (acute liver failure).
Cholestasis: altered bile flow → bilirubin accumulation.
Autoimmune: autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (→ cholangiocarcinoma).
Circulatory: portal vein thrombosis (benign), hepatic vein thrombosis (→ cirrhosis, HCC).

Laboratory Tests

Hepatocyte integrity: transaminases (LDH, ALT, AST); released from damaged/necrotic hepatocytes. AST > ALT in severe/alcoholic damage.
Bile secretion: conjugated/unconjugated bilirubin, bile acids, urine bilirubin; ALP, GGT (bile duct enzymes) ↑ in cholestasis.
Synthetic function: plasma proteins, albumin, coagulation factors, NH₃ (severity markers).

Mechanism of Liver Damage

Cell death (necrosis/apoptosis) from cholestasis, metabolic, ethanol, toxins, paracetamol, viral, thrombosis, autoimmune. Sudden → acute; gradual → chronic (→ HCC).

Acute Liver Damage

Harmful acute effect (ethanol, HAV, toxins, drugs).
Hepatocyte death → mediators (ROS, PAMP).
Kupffer cell + immune activation.
Phagocytosis + stellate cell activation (CCL2, PDGF, TGFβ) → ECM/growth factors for regeneration.
Stellate cell apoptosis.
Restitutio ad integrum (complete restoration if not too severe) — compensatory hyperplasia.

Chronic Liver Damage

Key = tissue remodeling (chronic alcoholism, HBV/HCV, NAFLD).

Damage → chronic inflammation.
Acute reconstructive mechanisms inhibited (no hepatocyte renewal).
Stellate cells → myofibroblasts → early fibrosis.
Fibrosis → disturbed blood flow → hypoxia → worsens inflammation (vicious cycle).
Advanced fibrosis → 6. cirrhosis.

Viral Hepatitis (DDx)

HAV: ssRNA, fecal-oral, incubation 2–6 wks, benign acute (no chronic), Dx serum IgM anti-HAV.
HBV: DNA, perinatal/sexual/IV, incubation 2–26 wks, asymptomatic carriage common → acute/chronic/HCC, Dx anti-HBsAg/HBcAg, DNA-PCR.
HCV: ssRNA, parenteral, incubation 4–26 wks, often asymptomatic acute (80–85%) → chronic, long-lasting carriage, Dx PCR.
Histology: T-lymphocyte infiltration, necrosis, apoptosis, bridging necrosis/fibrosis (chronic).

一問一答

▶Give examples of substances the liver inactivates versus activates.

Inactivates bilirubin, ammonia, and steroid hormones; activates vitamin D.

▶Name the metabolic (accumulation) causes of chronic liver disease.

NAFLD (lipids, from obesity/T2DM), hemochromatosis (iron), Wilson's disease (copper, AR), and α1-antitrypsin deficiency (protein, AR).

▶What are the main intermediary metabolic functions of the liver?

Carbohydrate (glycemic control, gluconeogenesis/glycolysis), lipid (VLDL production), and protein (albumin, coagulation factors, acute-phase proteins) metabolism.

▶What does the liver store?

Glycogen, vitamin A, and metals.

▶Which hepatitis viruses cause acute versus chronic disease?

HAV causes acute, benign disease (no chronic); HBV and HCV can become chronic, leading to cirrhosis and HCC.

▶Which toxic/drug causes produce acute versus chronic liver injury?

Alcohol causes chronic injury; paracetamol causes acute liver failure.

▶What are the autoimmune liver/biliary diseases?

Autoimmune hepatitis, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (which can lead to cholangiocarcinoma).

▶Which transaminases indicate hepatocyte integrity, and what pattern suggests severe/alcoholic damage?

ALT and AST (and LDH) are released from damaged hepatocytes; AST > ALT indicates severe or alcoholic damage.

▶Which enzymes rise in cholestasis?

ALP and GGT (bile duct enzymes).

▶Which lab markers reflect hepatic synthetic function?

Plasma proteins, albumin, coagulation factors, and ammonia (NH₃) — markers of severity.

▶Outline the steps of acute liver damage repair.

Harmful effect → hepatocyte death → mediators (ROS, PAMP) → Kupffer/immune activation → phagocytosis + stellate cell activation → stellate apoptosis → restitutio ad integrum (complete restoration if not too severe).

▶How does fibrosis create a vicious cycle in chronic liver damage?

Fibrosis disturbs blood flow → hypoxia → worsened inflammation → more fibrosis.

▶What is the key process in chronic liver damage?

Tissue remodeling: stellate cells become myofibroblasts producing fibrosis, ultimately leading to cirrhosis.

▶What converts stellate cells to fibrogenic cells, and via which mediators?

Activation into myofibroblasts, driven by mediators such as CCL2, PDGF, and TGFβ.

▶Characterize HAV (genome, transmission, course, diagnosis).

ssRNA virus; fecal-oral; incubation 2–6 weeks; benign acute disease with no chronic form; diagnosed by serum IgM anti-HAV.

▶Characterize HBV (genome, transmission, course, diagnosis).

DNA virus; perinatal/sexual/IV transmission; incubation 2–26 weeks; can be acute/chronic/HCC with common asymptomatic carriage; diagnosed by anti-HBsAg/HBcAg and DNA-PCR.

▶Characterize HCV (genome, transmission, course, diagnosis).

ssRNA virus; parenteral transmission; incubation 4–26 weeks; often asymptomatic acute (80–85%) progressing to chronic long-lasting carriage; diagnosed by PCR.

▶What endocrine products does the liver make?

Hormone precursors (vitamin D), growth factors (IGF-1/2), and hepcidin.

▶What are the circulatory causes of liver disease and their outcomes?

Portal vein thrombosis (benign) and hepatic vein thrombosis (can lead to cirrhosis and HCC).

▶What histological features characterize viral hepatitis?

T-lymphocyte infiltration, necrosis, apoptosis, and bridging necrosis/fibrosis in chronic disease.