Familial Hypercholesterolemia

Slide 1 · Familial

Hypercholesterolemia

Single-gene disruption of LDL clearance

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how LDL is produced and cleared by the liver.

Distinguish LDLR, APOB and PCSK9 mechanisms of FH.

Relate LDL receptor defects to xanthomas and premature atherosclerosis.

Classify six functional LDLR mutation categories.

Explain how statins and PCSK9 inhibition modify receptor availability.

Slide 3 · Familial hypercholesterolemia: The central defect

The primary lesion is inadequate receptor-mediated removal of plasma LDL.

Reduced LDLR function

Impaired hepatic uptake

Raised plasma LDL

Premature atherosclerosis

FH is a membrane-receptor trafficking disorder with systemic vascular consequences.

Slide 4 · A receptor-transport model of Mendelian disease

Molecular change

Functional effect

Altered receptor synthesis

Altered receptor targeting

Altered ligand binding

Altered endocytosis/recycling

Less effective hepatic LDL clearance

Accumulation of circulating LDL

Greater exposure of tissues to cholesterol

Accelerated atherogenesis

The site of the molecular lesion determines the specific transport failure.

Slide 5 · Autosomal dominant expression: One altered allele matters

One functional LDLR allele

~50% normal receptor number

LDL catabolism decreases

LDL rises

Heterozygotes express disease despite retaining one working copy of LDLR.

Reduced receptor dosage is sufficient to raise LDL from birth.

Slide 6 · Heterozygous and homozygous FH differ in severity

Feature

Heterozygous LDLR-associated FH

Homozygous LDLR-associated FH

Functional alleles

One retained

Usually none normally functioning

LDL receptors

Approximately 50% of normal

Virtually absent in severe forms

Plasma cholesterol

About 2–3× normal

About 5–6× normal

Atherosclerosis

Premature, usually adult manifestations

May appear in childhood

Myocardial infarction

Premature risk

May occur before age 20

Slide 7 · FH is genetically heterogeneous

LDLR

Receptor protein

Most common cause

Inadequate uptake

APOB

LDL ligand ApoB-100

Reduced receptor binding

Less removal

PCSK9

Regulator of LDLR turnover

Activating variants

Faster receptor loss

Different molecular defects converge on reduced LDLR-mediated clearance.

Slide 8 · Genetic contributions reported

Gene

Approximate proportion of FH cases

Proximal molecular effect

LDLR

80%–85%

Receptor deficiency or dysfunction

APOB

5%–10%

Weakened LDL–LDLR binding

PCSK9

1%–2%

Excess receptor degradation

These textbook figures describe distribution, not a diagnostic test.

Slide 9 · LDLR mutations reduce functional LDL receptors

LDLR mutation

Fewer effective receptors

Less liver uptake

Elevated plasma LDL

The receptor defect can alter synthesis, trafficking, binding, uptake or recycling.

Slide 10 · APOB mutations compromise receptor recognition

LDL particle

LDL receptor

Weakened ApoB-100

Interaction

A receptor can be present yet fail to efficiently capture altered LDL.

Slide 11 · PCSK9 gain of function removes LDL receptors

Activating PCSK9 variant

Increased LDLR degradation

Fewer surface LDLRs

Reduced LDL clearance

PCSK9 determines how often internalized receptors are recycled versus degraded.

Slide 12 · Three genes; One shared pathophysiologic endpoint

Lesion

Mechanistic location

Result

LDLR loss of function

The receptor itself

Reduced functional LDLR activity

APOB defective ligand

LDL particle surface

Less effective LDL attachment

PCSK9 gain of function

Receptor turnover

More LDLR lysosomal degradation

Slide 13 · The normal body cholesterol pool has two sources

Exogenous supply

Endogenous supply

Dietary triglycerides and cholesterol

Intestinal incorporation into chylomicrons

Chylomicron remnants reach liver

Hepatic cholesterol synthesis

Hepatic secretion of VLDL

Conversion through IDL to LDL

FH predominantly disrupts handling of circulating LDL, not dietary absorption alone.

Slide 14 · Dietary lipid delivery: The chylomicron route

1

Intestinal mucosa packages lipid as chylomicrons.

2

Chylomicrons enter lymphatics and then blood.

3

Lipoprotein lipase hydrolyzes their triglycerides in capillaries.

4

Cholesterol-rich remnants are delivered to the liver.

Chylomicron remnants feed the hepatic cholesterol pool.

Slide 15 · Hepatic VLDL secretion starts endogenous transport

VLDL particle

Triglyceride-rich lipoprotein

Carries ApoB, ApoC and ApoE

Secreted from the liver into blood

VLDL

VLDL is the immediate upstream precursor of IDL.

Slide 16 · Lipoprotein lipase converts VLDL into IDL

VLDL, TG-rich

Capillary lipolysis

IDL remnant

Less triglyceride

IDL retains ApoB and ApoE while ApoC is lost.

Slide 17 · IDL has two competing metabolic fates

IDL (ApoB + ApoE)

Hepatic LDLR

Clearance

Further metabolism

To LDL

The liver normally clears roughly half of newly formed IDL.

Slide 18 · LDL arises from further IDL processing

IDL

Further triglyceride removal

Loss of ApoE

Cholesterol-rich LDL

Mature LDL retains ApoB, which serves as the LDLR-recognition ligand.

Slide 19 · ApoB and ApoE have distinct ligand roles

Lipoprotein

Relevant apolipoproteins

LDLR recognition

VLDL

ApoB, ApoC, ApoE

Precursor of IDL

IDL

ApoB and ApoE

LDLR recognizes both ligands

LDL

ApoB retained

LDLR binds via ApoB

Slide 20 · The liver is the dominant organ of LDL clearance

~70%

Of plasma LDL is normally cleared by the liver

Hepatic LDLR function is therefore a major determinant of LDL residence in plasma.

Slide 21 · LDLR-mediated uptake begins at the cell surface

LDL (ApoB)

LDL receptor

Specific ApoB–LDLR

Recognition

Mutant ligand or receptor can disrupt this first step.

Slide 22 · Coated pits concentrate LDL receptor complexes

Surface LDLR + LDL

Clathrin-coated pit

Coated vesicle

Internalization

Clathrin-mediated uptake is downstream of surface binding.

Slide 23 · Endosomal trafficking separates ligand and receptor

1

Receptor-bound LDL enters a coated vesicle.

2

The vesicle traffics into the endosomal compartment.

3

LDL dissociates from its receptor.

4

LDLR is sorted for recycling or, under PCSK9 influence, degradation.

Effective recycling preserves hepatocyte surface receptor density.

Slide 24 · Lysosomes process internalized LDL

Internalized LDL

Lysosomal hydrolysis

Amino acids + free cholesterol

ApoB is degraded to amino acids; Cholesteryl esters yield free cholesterol.

Slide 25 · Receptor recycling sustains repeated LDL uptake

LDLR at membrane

Internalization

Ligand release

Receptor recycling

LDLR at membrane

Recycling is a distinct vulnerability from initial LDL binding.

Slide 26 · NPC1 and NPC2 help cholesterol exit lysosomes

LDL hydrolysis

Free lysosomal cholesterol

NPC1 / NPC2 action

Cytoplasmic cholesterol

Intracellular cholesterol then enters biosynthesis and regulatory pathways.

Slide 27 · Cellular cholesterol provides feedback control

Intracellular free cholesterol

↓ HMG-CoA reductase

↑ Cholesterol ester storage

↓ LDL receptor synthesis

↑ PCSK9-mediated LDLR degradation

Slide 28 · Cholesterol inhibits de novo synthesis

More cellular cholesterol

HMG-CoA reductase inhibited

Less cholesterol synthesis

This feedback constrains endogenous synthesis when cellular cholesterol is plentiful.

Slide 29 · Excess cholesterol can be stored as esters

Free cholesterol

ACAT activity increases

Esterification

Storage

ACAT: Acyl-coenzyme A:cholesterol acyltransferase.

Slide 30 · High cellular cholesterol suppresses LDLR synthesis

High intracellular cholesterol

Less LDLR synthesis

Less LDL uptake

LDLR expression responds to cholesterol supply within the cell.

Slide 31 · PCSK9 adds a receptor-degradation feedback

Elevated cell cholesterol

PCSK9 expression increases

LDLR degradation increases

LDL uptake falls

PCSK9 regulates receptor availability after endocytosis.

Slide 32 · Cholesterol homeostasis integrates supply and uptake

Intracellular cholesterol

Synthesis ↓

Ester storage ↑

LDLR synthesis ↓

Recycling ↓ via PCSK9

Four responses limit further accumulation of free intracellular cholesterol.

Slide 33 · LDLR loss impairs plasma LDL catabolism

Normal hepatocyte

FH-affected hepatocyte

Many functional LDL receptors

Effective binding and internalization

Continuous receptor recycling

Lower circulating LDL

Fewer effective LDL receptors

Inadequate receptor-mediated uptake

Slower LDL clearance

Elevated circulating LDL

Slide 34 · LDLR deficiency also increases LDL formation

Defective IDL clearance

More IDL remains in blood

More IDL processed to LDL

LDL pool increases

Elevated LDL is not solely failure of LDL uptake; Precursor diversion contributes.

Slide 35 · The FH phenotype has two reinforcing components

LDL clearance

Decreases

IDL → LDL

Conversion increases

Circulating LDL rises

Slide 36 · Normal and FH LDL trafficking compared

Normal LDL transport

Familial hypercholesterolemia

LDL binds LDLR

Complex internalizes

LDL is degraded

Receptor returns to membrane

Receptor number or function is reduced

LDL remains in circulation

IDL clearance also falls

Cholesterol accumulates in plasma

Slide 37 · Modified LDL enters macrophages by scavenger pathways

Chemically altered LDL

Scavenger receptors

Monocytes / macrophages

Cholesterol accumulation

Enhanced scavenger uptake in hypercholesterolemia.

Slide 38 · Macrophage lipid loading contributes to xanthomas

1

Plasma LDL remains substantially elevated.

2

A portion of LDL undergoes chemical alteration.

3

Mononuclear phagocytes take up altered LDL via scavenger receptors.

4

Accumulated lipid contributes to xanthoma formation.

Xanthomas are a clinical manifestation of tissue cholesterol deposition.

Slide 39 · Tendinous xanthomas are a hallmark of heterozygous FH

Textbook phenotype: Tendon xanthomas accompanying lifelong hypercholesterolemia.

Clinicopathologic interpretation

Visible tendon lipid deposition reflects chronic excess cholesterol.

Presence increases suspicion for inherited LDL dysregulation.

Absence does not logically exclude molecular disease.

Slide 40 · LDL excess accelerates atherosclerosis

Sustained high LDL

Vascular wall lipid traffic

Atherosclerotic lesions

Ischemic complications

Pathologic vascular consequences explain the importance of early detection.

Slide 41 · Heterozygous FH often becomes evident in adult life

1

Lifelong elevation of plasma cholesterol begins at birth.

2

Tendon xanthomas may emerge with prolonged exposure.

3

Premature atherosclerosis develops over time.

4

Coronary complications become a major clinical concern.

Clinical recognition may occur long after the biochemical abnormality begins.

Slide 42 · Severe biallelic FH can present in childhood

1

Very high LDL exposure starts early in life.

2

Skin xanthomas may appear at a young age.

3

Coronary, cerebral and peripheral vascular disease can develop early.

4

Myocardial infarction can occur before age 20.

The earlier vascular phenotype reflects an extreme receptor-defect burden.

Slide 43 · Clinical severity tracks the functional receptor deficit

Molecular background

Receptor activity

Expected phenotype

One affected LDLR allele

Reduced (~half normal receptors)

High LDL; premature adult disease

Two severely affected LDLR alleles

Virtually absent normal receptors

Marked LDL elevation; childhood disease

APOB ligand defect

Receptors poorly capture LDL

Elevated LDL via defective binding

PCSK9 activating variant

Receptors preferentially degraded

Elevated LDL via receptor scarcity

Slide 44 · Premature myocardial infarction is the major warning

Persistent LDL elevation promotes premature vascular atherosclerosis.

Coronary

Atherosclerosis

Risk of

Myocardial infarction

FH among 3%–6% of survivors of myocardial infarction.

Slide 45 · Lipid elevation should trigger an inherited-disease hypothesis

1

Recognize unusually high LDL cholesterol as a possible lifelong process.

2

Ask whether there is a family pattern of early vascular disease.

3

Assess visible tendon or skin xanthomas when present.

4

Consider the molecular mechanisms capable of impairing LDL clearance.

This is a mechanistic reasoning framework, not formal diagnostic criteria.

Slide 46 · Class I LDLR mutations: No receptor synthesis

Defective step: Synthesis

Synthesis

Transport

Binding

Endocytosis

Recycling

Class I: Failure of LDL receptor protein synthesis

A receptor is not produced and therefore cannot reach the cell surface.

Class I as relatively uncommon.

Slide 47 · Class II LDLR mutations: Retention in endoplasmic reticulum

Defective step: ER-to-Golgi trafficking

Synthesis

Transport

Binding

Endocytosis

Recycling

Class II: Mutant LDLR remains in the ER

Folding defects or truncations prevent normal transport to the Golgi.

Surface receptor availability is reduced despite attempted synthesis.

Slide 48 · Class III LDLR mutations: Defective ligand binding

Defective step: Ligand attachment

Synthesis

Transport

Binding

Endocytosis

Recycling

Class III: Mutant LDLR binds LDL poorly or not at all

Receptors reach the surface but have an ineffective ApoB-binding site.

Surface expression does not guarantee uptake.

Slide 49 · Class IV LDLR mutations: Impaired coated-pit localization

Defective step: Internalization

Synthesis

Transport

Binding

Endocytosis

Recycling

Class IV: Receptors fail to enter coated pits

Mutant receptors reach the surface and bind ligand normally.

Defective localization blocks uptake of receptor-bound LDL.

Slide 50 · Class V LDLR mutations: Defective endosomal recycling

Defective step: Recycling

Synthesis

Transport

Binding

Endocytosis

Recycling

Class V: Ligand dissociation in the endosome fails

The receptor–LDL complex is diverted toward degradation rather than reuse.

LDL binding and initial internalization can remain intact.

Slide 51 · Class VI LDLR mutations: Mistargeting at the hepatocyte surface

Defective step: Membrane targeting

Synthesis

Transport

Binding

Endocytosis

Recycling

Class VI: Receptor is missorted to the apical surface

Poor receptor availability at the sinusoidal interface impairs plasma LDL uptake.

Class VI was not depicted’s original figure 5.9.

Slide 52 · Functional classes I–VI of LDLR variants

Class

Defective operation

Functional consequence

I

Receptor synthesis

No LDLR protein

II

ER-to-Golgi trafficking

Intracellular retention

III

LDL / ApoB binding

Weak or absent ligand binding

IV

Coated-pit localization

Failed internalization

V

Endosomal dissociation/recycling

Reduced recycling

VI

Basolateral membrane targeting

Mislocalized surface receptor

Slide 53 · Every LDLR class maps to one vulnerable transport step

1

Class I: Receptor never synthesized.

2

Class II: Receptor retained before reaching Golgi.

3

Class VI: Receptor fails to target the basolateral membrane.

4

Class III: Cell-surface receptor cannot bind LDL effectively.

5

Class IV: Receptor–LDL complex fails to enter coated pits.

6

Class V: Internalized receptor fails to recycle efficiently.

Transport sequence clarifies why all six classes produce LDL accumulation.

Slide 54 · Case application: Altered ligand versus altered receptor

A person has inherited hypercholesterolemia. The LDL receptor is present at the hepatocyte membrane, but LDL particles bind inefficiently.

Which gene mechanism most directly explains defective ligand function?

APOB: Altered ApoB-100 reduces LDL binding to the receptor.

Slide 55 · Case application: Preserved binding, failed internalization

Mutant LDL receptors appear on the cell surface and bind LDL normally, but receptor-bound LDL is not effectively internalized.

Which class of LDLR functional defect is implicated?

Class IV: Defective coated-pit localization and endocytosis.

Slide 56 · Statins decrease intracellular cholesterol synthesis

HMG-CoA reductase inhibited

Cellular cholesterol falls

LDLR expression rises

Plasma LDL clearance rises

Statin benefit includes increased hepatocyte surface LDL receptors.

Slide 57 · PCSK9 inhibition preserves LDL receptor recycling

PCSK9 action blocked

Less LDLR degradation

More surface LDLRs

Increased LDL removal

The intervention acts on receptor turnover rather than ApoB synthesis.

Slide 58 · Natural PCSK9 loss of function validates its biology

1

PCSK9 was implicated through individuals with very low serum cholesterol.

2

These individuals carried loss-of-function PCSK9 variants.

3

Reduced PCSK9 activity permits increased availability of LDL receptors.

4

The observation supported development of PCSK9-targeted treatment.

Human genetic variation helped expose a therapeutically actionable mechanism.

Slide 59 · Two therapeutic mechanisms increase effective LDLR availability

Strategy

Initial molecular target

Effect on LDLR

Result

Statin

HMG-CoA reductase

Increased receptor synthesis

Greater LDL clearance

PCSK9 inhibition

PCSK9-mediated degradation

Reduced receptor destruction

Greater LDL clearance

Both mechanisms rely on functional receptor-mediated LDL disposal.

Slide 60 · Molecular phenotype predicts pathway dependence

Relevant question

Implication

Is receptor synthesis retained?

Can the receptor reach the correct surface?

Does it bind LDL?

Can it internalize and recycle?

Therapies that raise receptor abundance require usable LDLR function.

A near-null receptor state differs mechanistically from partial receptor function.

Variant class gives biological context—not a treatment prescription.

Slide 61 · Integrated pathogenesis: From gene to vascular disease

LDLR / APOB / PCSK9

Impaired hepatic LDL uptake

Lifelong plasma LDL excess

Xanthomas + atherosclerosis

FH exemplifies how a single molecular pathway produces multisystem pathology.

Slide 62 · Five essential concepts to retain

LDLR-dependent hepatic removal governs plasma LDL exposure.

LDLR, APOB and PCSK9 defects converge on impaired LDL clearance.

LDLR deficiency diverts IDL toward LDL and slows LDL disposal.

Six LDLR classes correspond to different cellular transport failures.

Xanthomas and premature atherosclerosis follow sustained LDL excess.

Slide 63 · References and source limitations

Primary teaching source

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. (2026). Chapter 5, “Genes and Human Diseases,” pp. 127–134.

Scope and verification

Prepared from the supplied Robbins Markdown text and topic archive.

Original chapter PDF and textbook figures were not available for page-image verification.

Diagrams are newly authored PowerPoint schematics, not reproduced textbook figures.

Clinical diagnostic criteria and current treatment guidelines are deliberately outside this source-derived lecture.