Toxic Myopathies and Myopathy With Metabolic Changes

Slide 1 · Toxic Myopathies and

Myopathy With Metabolic Changes

Pathologic mechanisms · Morphology · Clinicopathologic interpretation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Different mechanisms can yield the same clinical presentation.

Classify drug- and hormone-associated muscle injury by its primary cellular target.

Explain muscle necrosis, vacuolation, selective atrophy, and thick-filament loss.

Distinguish direct drug toxicity from immune-mediated necrotizing myopathy.

Apply exposure history and morphology to focused diagnostic reasoning.

Slide 3 · Scope: Acquired muscle disease

Medications, non-medicinal substances, and hormonal states may produce weakness and muscle injury.

The effects are not restricted to one pathologic mechanism.

Some exposures cause myofiber necrosis; Others preferentially injure organelles.

Still others produce fiber-type-selective atrophy or sarcomeric protein loss.

Creatine kinase (CK) may rise with muscle damage, but phenotypes differ.

Slide 4 · Six mechanisms at a glance

Mechanism

Representative exposure

Pathologic emphasis

Direct myonecrosis

Statins · fibrates · high-dose alcohol

Myofiber necrosis

Immune mediated

Statins · checkpoint inhibitors

Necrosis with limited inflammation in IMNM

Mitochondrial

Zidovudine

Organelle injury

Lysosomal

Hydroxychloroquine · chloroquine

Vacuolar change

Protein catabolism

Corticosteroids · critical illness

Type II atrophy or myosin depletion

Hormonal

Thyroid excess or deficiency

Functional and structural changes

Slide 5 · The exposure-to-phenotype framework

Drug or hormonal exposure

Dominant cellular target

Characteristic tissue response

Clinical weakness ± CK elevation

Mechanistic relationship—not a diagnostic algorithm

A common symptom need not imply a common mechanism.

Slide 6 · Weakness and CK are not the mechanism

Observation

What it establishes

What it does not establish

Proximal weakness

A clinically important functional deficit

Whether the cause is necrotic, atrophic, or organellar

Elevated serum CK

Leakage of muscle cytoplasmic enzyme

A unique etiology or immune pathogenesis

Drug exposure

A plausible cause to investigate

Proof of direct toxicity without further correlation

Slide 7 · Why damaged myofibers release CK

Segmental myofiber injury

Loss of membrane integrity

Release of cytoplasmic CK

Detectable serum elevation

Mechanistic relationship—not a diagnostic algorithm

CK is a marker of damaged muscle, not a mechanism-specific biomarker.

Slide 8 · Necrosis, myophagocytosis, regeneration

Focal segmental necrosis

Macrophage removal of debris

Satellite-cell participation

Reconstruction of sarcomeres

Mechanistic relationship—not a diagnostic algorithm

Regeneration follows clearance of necrotic myofiber material.

Slide 9 · Interpret CK within the muscle phenotype

CK elevation is clinically useful, but its interpretation depends on the associated pattern.

Direct myofiber necrosis can release abundant cytoplasmic enzymes.

Morphologic fiber atrophy is mechanistically different from fiber necrosis.

A toxic exposure and an immune-mediated process may initially resemble one another.

Integrate exposure, weakness, muscle morphology, and the clinical course.

Slide 10 · Acute myonecrotic agents

Agent / class

Source-supported association

Clinical implication

Statins

Acute necrosis of individual fibers

Rhabdomyolysis possible when severe

Fibrates

Acute myofiber injury and necrosis

Consider in drug exposure history

High-dose alcohol

Acute myofiber injury and necrosis

Non-medicinal exposure may be relevant

Slide 11 · Direct toxicity: Segmental injury

Injurious exposure

Necrosis of individual myofibers

Muscle breakdown and CK release

Weakness; Severe cases may progress

Mechanistic relationship—not a diagnostic algorithm

“Direct” refers to toxic myofiber injury, not to a biopsy pattern uniquely diagnostic of a drug.

Slide 12 · Severe myonecrosis may become rhabdomyolysis

Widespread muscle breakdown

Rhabdomyolysis

Systemic complications

Potential acute renal failure

Mechanistic relationship—not a diagnostic algorithm

The renal complication is explicitly emphasized; No incidence or threshold is specified.

Slide 13 · Renal risk is a major consequence

The severity of myofiber necrosis determines whether the problem remains localized or becomes systemic.

Rhabdomyolysis is a severe form of muscle breakdown.

Acute renal failure is a recognized complication.

Clinical assessment must therefore extend beyond limb weakness.

The source does not specify CK cutoffs or a treatment algorithm.

Slide 14 · Direct statin toxicity: Predisposing factors

Increased risk of direct statin toxicity

Higher statin dose

Age >65 years

Renal failure

Hepatic failure

Hypothyroidism

Slide 15 · Statin exposure is not one phenotype

The same drug class can be associated with different causal pathways.

Direct statin myotoxicity is dose- and host-factor-associated.

Statin exposure may also be associated with immune-mediated necrotizing myopathy.

The initial presentation may not distinguish these mechanisms reliably.

Risk factors for direct toxicity should not be equated with diagnostic criteria for IMNM.

Slide 16 · Expected course of direct toxicity

Identify an offending agent

Discontinue that exposure

Provide supportive care

Patients typically improve

Mechanistic relationship—not a diagnostic algorithm

A typical improvement after withdrawal; It does not guarantee full or immediate recovery.

Slide 17 · Case 1 · suspected direct myonecrosis

HYPOTHETICAL PRESENTATION

An older adult taking a statin develops new muscle weakness with elevated CK. Renal impairment and hypothyroidism are also present.

Which source-supported factors strengthen the possibility of direct statin toxicity?

REASONING PROMPTS

Drug dose matters.

Age over 65, renal failure, and hypothyroidism are recognized risk factors.

Slide 18 · Case 1 · reasoning

The exposure and host factors support a direct toxic pathway, but they do not prove it.

Higher statin dose is associated with greater direct toxicity risk.

Renal failure and hypothyroidism are additional risk factors.

Severe necrotic injury warrants attention to rhabdomyolysis and renal effects.

A distinct immune-mediated pathway remains part of the differential.

Slide 19 · Immune-mediated drug-associated myopathy

Exposure

Robbins association

Interpretive issue

Statins

May trigger immune-mediated myopathy

Direct toxicity versus IMNM

Immune checkpoint inhibitors

May trigger immune-mediated myopathy

Exposure alone does not define subtype

No preceding statin exposure

Anti-HMGCR IMNM can still occur

Statin history is not obligatory

Slide 20 · Two routes from statin exposure

Statin exposure

Direct toxic myonecrosis

Dose and host factors

Typical improvement after withdrawal

Immune-mediated necrotizing myopathy

Anti-HMGCR association possible

Differentiation may be difficult initially

Slide 21 · IMNM: Tissue injury out of proportion to inflammation

Immune-mediated necrotizing myopathy (IMNM) is defined by prominent myofiber necrosis.

Typically high CK and rapidly progressive weakness.

Necrotic and regenerating fibers are randomly intermixed.

Associated inflammatory infiltrates may be sparse.

Minimal inflammation therefore does not by itself exclude an immune process.

Slide 22 · Anti-HMGCR myopathy and statin history

Antibodies to HMG-CoA reductase occur in a subset of IMNM.

HMG-CoA reductase is involved in cholesterol synthesis.

Antibodies are described in patients previously exposed to statins.

They are also described in statin-naïve patients.

Never use statin exposure alone as a requirement for this antibody-associated phenotype.

Slide 23 · Anti-SRP: A separate IMNM association

Antibodies to the signal recognition particle (SRP) identify another associated IMNM group.

Anti-SRP IMNM may be especially severe.

Dysphagia occurs more often in this subset.

Cardiac involvement may develop.

These features provide context, but the lecture remains focused on toxic and metabolic myopathies.

Slide 24 · Checkpoint inhibitors and immune injury

Immune checkpoint inhibitors are another medication class implicated in immune-mediated myopathy.

The defining issue is immune-associated muscle damage, not direct organelle toxicity.

The exact pathology and severity must be established in the affected patient.

Robbins gives the association without drug-specific diagnostic cutoffs.

Avoid assuming that every affected patient has anti-HMGCR or anti-SRP antibodies.

Slide 25 · Direct statin toxicity versus IMNM

Feature

Direct toxic pathway

Immune-mediated necrotizing pathway

Pathogenesis

Myofiber-toxic injury

Immune-mediated muscle injury

Clinical pattern

Weakness and CK elevation

Often severe weakness and high CK

Biopsy concept

Necrosis may occur

Prominent necrosis / regeneration; sparse inflammation

Drug withdrawal

Typical improvement with withdrawal

Cannot be assumed sufficient from exposure alone

Slide 26 · Case 2 · severe weakness after statin exposure

HYPOTHETICAL PRESENTATION

A person receiving a statin develops rapidly progressive weakness and a striking CK elevation. Biopsy shows scattered necrotic and regenerating myofibers with little inflammation.

Which competing pathway deserves attention?

REASONING PROMPTS

Necrotizing morphology with sparse inflammation can occur in IMNM.

Statin exposure also permits direct toxicity.

Slide 27 · Case 2 · pathologic interpretation

Do not infer direct drug toxicity merely because a statin preceded the myopathy.

The biopsy pattern is compatible with IMNM in the appropriate setting.

Sparse inflammatory cells do not disprove an immune-mediated necrotizing process.

Anti-HMGCR and anti-SRP are relevant antibody associations in the adjacent Robbins section.

Clinical evaluation must distinguish the processes rather than collapse them.

Slide 28 · Mitochondria are another drug target

A toxic myopathy can result from injury to an intracellular energy-producing organelle.

Zidovudine as an acquired mitochondrial myopathy exposure.

This mechanism differs from sarcolemmal injury with acute necrosis.

Inherited mitochondrial disorders also exist, but are a separate etiologic category.

The central diagnostic task is to match the exposure to the mechanism.

Slide 29 · Zidovudine and acquired mitochondrial injury

Antiretroviral exposure: Zidovudine

Mitochondrial damage

Acquired mitochondrial myopathy

Muscle dysfunction

Mechanistic relationship—not a diagnostic algorithm

The source identifies this association; No frequency or exposure threshold is given.

Slide 30 · Energy generation and muscle function

Intact mitochondria

ATP generation

Energy-dependent contraction

Normal skeletal muscle function

Mechanistic relationship—not a diagnostic algorithm

Mitochondrial disease can compromise ATP production. This is a general concept from the adjacent Robbins mitochondrial section.

Slide 31 · Acquired versus inherited mitochondrial myopathy

Dimension

Acquired drug-associated

Inherited mitochondrial disease

Initiating cause

Exogenous mitochondrial toxicant

Pathogenic genetic alteration

Example or context

Zidovudine exposure

Nuclear or mitochondrial genes

Teaching boundary

A toxic myopathy subtype

Separate inherited disease topic

Slide 32 · Case 3 · a mitochondrial exposure clue

HYPOTHETICAL PRESENTATION

A patient using zidovudine develops muscle weakness. The team considers a medication-associated acquired mitochondrial myopathy.

Which cellular target is explicitly associated with this medication?

REASONING PROMPTS

Mitochondria are the implicated target.

Do not infer a particular genetic defect from the drug history.

Slide 33 · Lysosomal dysfunction: A different route

Drug interference with lysosomes

Accumulation of membranous material

Vacuolar myopathic change

Insidious muscle dysfunction

Mechanistic relationship—not a diagnostic algorithm

The source describes lysosomal-storage-disease-like changes, not inherited storage disease.

Slide 34 · Chloroquine and hydroxychloroquine

These agents may cause insidious toxic myopathy through interference with lysosomal function.

The clinical time course may be gradual rather than acutely necrotizing.

Muscle pathology can resemble a lysosomal storage disorder.

Vacuoles are a major tissue clue.

Cardiac muscle may show a similar drug-related process.

Slide 35 · Vacuoles as the light-microscopic clue

READING THE SCHEMATIC

1. Myofiber cross-section

2. Intracytoplasmic vacuoles

3. Interpret with medication history

Conceptual schematic: Intrafiber vacuolation; Not a real histologic specimen.

Slide 36 · Type I fibers are preferentially involved

READING THE SCHEMATIC

1. Type I fibers: Preferential vacuolation

2. Type II fibers: Less prominently affected

3. Fiber typing provides mechanistic context

Conceptual fiber-type map; Not an ATPase-stained biopsy.

Slide 37 · Lamellar inclusions on electron microscopy

READING THE SCHEMATIC

1. Whorled lamellar membranous aggregates

2. Ultrastructural correlate of organelle injury

3. Do not equate with every rimmed vacuole

Native vector schematic of membrane whorls; Not an electron micrograph.

Slide 38 · Why the heart also matters

The pathologic effect of lysosomal-toxic medication exposure is not necessarily confined to skeletal muscle.

Cardiac involvement with chloroquine or hydroxychloroquine.

Cardiac muscle may exhibit similar pathologic changes.

A skeletal-muscle-focused history can miss this extra-skeletal dimension.

The source gives no specific cardiac prevalence or screening protocol.

Slide 39 · Acquired vacuolar change versus storage disease

Feature

Drug-related lysosomal dysfunction

Inherited lysosomal storage condition

Proposed etiology

Drug interference with lysosomes

An inherited metabolic mechanism

Biopsy overlap

Vacuolation / membranous aggregates

May resemble vacuolar myopathy

Key discriminant

Drug history and disease context

Independent evaluation of inherited disease

Slide 40 · Case 4 · vacuoles on muscle biopsy

HYPOTHETICAL PRESENTATION

A patient on prolonged hydroxychloroquine therapy develops slowly progressive weakness. Muscle biopsy shows vacuolation; Whorled lamellar membrane structures are seen on electron microscopy.

What is the most coherent mechanism?

REASONING PROMPTS

The drug can interfere with lysosomal function.

The acquired condition may mimic a lysosomal storage disease.

Slide 41 · Case 4 · interpreting the biopsy

The combination of exposure, course, and morphology favors a drug-associated lysosomal lesion.

Insidious onset fits chloroquine/hydroxychloroquine-associated myopathy.

Vacuoles preferentially involve type I fibers in the Robbins description.

Lamellar membranous material is the ultrastructural clue.

The pathologist should avoid diagnosing inherited storage disease solely from a vacuolated fiber.

Slide 42 · Corticosteroids: A catabolic muscle phenotype

Endogenous and exogenous catabolic corticosteroid exposure can lead to muscle weakness.

The hallmark change is selective type II myofiber atrophy.

Proximal weakness is the common functional correlate.

This is a predominantly atrophic pattern rather than a primary vacuolar one.

The morphologic target helps separate it from acute myonecrosis.

Slide 43 · Steroid effect: Protein balance to atrophy

Catabolic corticosteroid state

Selective type II fiber atrophy

Reduced contractile muscle capacity

Proximal weakness

Mechanistic relationship—not a diagnostic algorithm

Schematic causal organization of the source-described association.

Slide 44 · Type II fiber atrophy: Selective pattern

READING THE SCHEMATIC

1. Type II fibers reduced in diameter

2. Type I fibers relatively preserved

3. Compare with drug-related vacuolation of type I fibers

Conceptual type I/type II fiber map; Not clinical histology.

Slide 45 · Proximal weakness has multiple causes

Proximal weakness alone is insufficient to assign a drug mechanism.

Corticosteroid states: Selective type II atrophy.

Thyrotoxicosis: Proximal weakness may be acute or chronic.

Toxic necrosis: Individual myofiber damage and CK leakage.

Immune-mediated necrotizing myopathy: Severe weakness with prominent necrosis.

Slide 46 · Critical illness myopathy: Clinical setting

A distinct acquired neuromuscular disorder may arise in critically ill patients in the intensive care unit.

Robbins also calls it myosin-deficient myopathy.

A described context includes corticosteroids and depolarizing neuromuscular blocking agents.

Mechanical ventilation is part of the clinical setting.

Profound weakness can become an obstacle to recovery.

Slide 47 · Critical illness: Myosin thick-filament loss

Intact sarcomere: Thick-filament zone

Myosin-deficient state: Fewer thick filaments

READING THE SCHEMATIC

1. Relatively selective myosin thick-filament degradation

2. Loss of contractile protein content

3. Severe functional muscle weakness

Simplified sarcomere illustration; Spacing is schematic, not ultrastructural evidence.

Slide 48 · Why ventilator weaning becomes difficult

Critical illness / ICU treatment context

Myosin thick-filament depletion

Profound muscle weakness

Difficulty weaning from ventilation

Mechanistic relationship—not a diagnostic algorithm

This is a clinically important consequence explicitly cited.

Slide 49 · Steroid myopathy versus critical illness myopathy

Feature

Catabolic steroid myopathy

Critical illness myopathy

Setting

Endogenous or exogenous steroid excess

Severe ICU illness and treatment context

Dominant morphologic change

Selective type II atrophy

Relatively selective thick-filament myosin loss

Clinical consequence

Proximal weakness

Profound weakness, difficult ventilator liberation

Slide 50 · Case 5 · ICU weakness

HYPOTHETICAL PRESENTATION

A ventilated ICU patient receiving corticosteroids and depolarizing neuromuscular blockers has profound weakness that impedes ventilator weaning.

Which named pathologic phenotype is emphasized?

REASONING PROMPTS

Critical illness / myosin-deficient myopathy.

Relatively selective loss of sarcomeric myosin thick filaments.

Slide 51 · Thyroid disease belongs in this differential

Thyroid dysfunction causes acquired myopathic changes without requiring an exogenous medication.

Both excess and deficiency of thyroid hormone are associated with muscle symptoms.

The weakness pattern and associated systemic findings differ.

Hypothyroidism also has specific tissue changes described in the source.

Do not assume all endocrine myopathy produces the same biopsy signature.

Slide 52 · Thyrotoxic myopathy

Thyroid-hormone excess commonly produces acute or chronic proximal weakness.

Weakness may arise before other obvious signs of hyperthyroidism.

Both acute and chronic presentations are recognized.

A proximal pattern can resemble medication-associated weakness.

The temporal order of symptoms is therefore diagnostically relevant.

Slide 53 · The diagnostic trap in thyrotoxicosis

New proximal weakness

Few obvious systemic clues

Consider thyroid dysfunction

Recognize thyrotoxic myopathy

Mechanistic relationship—not a diagnostic algorithm

The source emphasizes that weakness can precede typical hyperthyroid manifestations.

Slide 54 · Exophthalmic ophthalmoplegia: Described findings

A characteristic ocular syndrome that can accompany thyrotoxic myopathy.

Swelling of the eyelids.

Edema of the conjunctiva.

Diplopia.

These features are clinical clues to the associated thyroid disorder.

Slide 55 · Hypothyroid muscle symptoms

Thyroid-hormone deficiency can produce an aching, slow-moving muscular phenotype.

Muscular cramping and aching may be prominent.

Movement can become slow.

Reflex responses may be slowed.

Symptoms should be correlated with thyroid dysfunction before attributing them to a primary myopathy.

Slide 56 · Hypothyroid myopathy: Structural changes

READING THE SCHEMATIC

1. Myofiber atrophy and abnormally located nuclei

2. Glycogen aggregates

3. Occasional connective-tissue mucopolysaccharides

Native illustration of reported findings; Not a tissue photomicrograph.

Slide 57 · Thyrotoxic versus hypothyroid myopathy

Feature

Thyroid excess

Thyroid deficiency

Common muscle presentation

Acute or chronic proximal weakness

Aching, cramping, slowing of movement

Associated clue

May precede other hyperthyroid signs; ocular findings

Slowed reflexes

Tissue changes highlighted

Not specified in this source section

Atrophy, internal nuclei, glycogen, occasional mucopolysaccharide

Slide 58 · Morphology-to-exposure crosswalk

Morphologic feature

Most relevant category

Important caution

Myofiber necrosis

Acute toxic injury or IMNM

Necrosis does not identify mechanism alone

Type I vacuolation

Chloroquine / hydroxychloroquine

Can mimic a storage disorder

Type II atrophy

Corticosteroid state

Different from thick-filament depletion

Myosin thick-filament loss

Critical illness myopathy

Interpret in ICU context

Glycogen aggregates + atypical nuclei

Hypothyroid myopathy

Integrate clinical endocrine findings

Slide 59 · A mechanism-first diagnostic approach

Define weakness pattern and clinical setting

Review drugs, substances, and hormonal states

Interpret CK and tissue injury pattern

Match findings to a mechanism

Mechanistic relationship—not a diagnostic algorithm

An educational reasoning scheme derived from the source; Not a formal diagnostic guideline.

Slide 60 · Common interpretive pitfalls

Avoid confusing a reproducible histologic finding with a unique diagnosis.

High CK plus statin exposure does not prove a direct toxic pathway.

Little inflammation does not rule out IMNM.

Vacuoles do not, on their own, diagnose an inherited lysosomal disease.

Proximal weakness occurs in steroid, thyroid, and necrotizing processes.

ICU weakness must be considered in the critical-illness context.

Slide 61 · Rapid recognition: Six clinical clues

Clue

Mechanism to consider

Characteristic associated finding

Higher-dose statin + risk factors

Direct necrotic toxicity

CK elevation ± rhabdomyolysis

Statin + rapidly progressive weakness

Immune-mediated myopathy

Necrotizing biopsy pattern possible

Zidovudine exposure

Mitochondrial damage

Acquired mitochondrial myopathy

Hydroxychloroquine + vacuoles

Lysosomal dysfunction

Lamellar ultrastructure

Prolonged catabolic corticosteroid state

Selective type II atrophy

Proximal weakness

ICU + difficult weaning

Myosin-deficient myopathy

Thick-filament depletion

Slide 62 · Integrative problem · the vacuolar trap

HYPOTHETICAL PRESENTATION

Biopsy of a weak patient shows vacuoles. A preliminary report suggests “storage disease.” Medication review reveals hydroxychloroquine therapy.

Which one additional observation would reinforce an acquired toxic pathway?

REASONING PROMPTS

Whorled lamellar membranous structures on ultrastructure.

A type I–predominant vacuolar pattern.

Slide 63 · Interpretation · vacuolar differential

Drug-mediated lysosomal impairment is an important acquired mimic of metabolic storage disease.

Hydroxychloroquine/chloroquine history has high etiologic relevance.

Type I–predominant vacuolation matches the cited Robbins morphology.

Lamellar membrane whorls reinforce lysosomal dysfunction.

The clinical–pathologic synthesis must precede labeling an inherited condition.

Slide 64 · Integrative problem · proximal weakness

HYPOTHETICAL PRESENTATION

Two adults present with proximal weakness. One receives long-term corticosteroids; The other has hyperthyroidism with few obvious systemic signs.

Why does the shared clinical pattern not establish a shared pathologic process?

REASONING PROMPTS

Corticosteroid exposure favors selective type II fiber atrophy.

Thyrotoxic myopathy can precede obvious hyperthyroid signs.

Slide 65 · Interpretation · phenotype versus etiology

Proximal weakness is a localization pattern, not a causal classification.

A steroid-associated atrophic mechanism is one explanation.

A thyroid-related functional myopathy is another.

Necrotic and immune-mediated muscle diseases can also weaken proximal muscles.

Exposure, clinical context, and pathology must be read together.

Slide 66 · Summary: Injury target determines the clue

Cellular target

Exposure class

Teaching clue

Myofiber

Statin / fibrate / high-dose alcohol

Necrosis and CK release

Immune-associated injury

Statin / checkpoint inhibitor

Consider necrotizing immune myopathy

Mitochondrion

Zidovudine

Acquired organelle damage

Lysosome

Chloroquine / hydroxychloroquine

Vacuoles and lamellar aggregates

Fiber protein / sarcomere

Steroid state / critical illness

Type II atrophy or myosin loss

Endocrine-regulated muscle

Thyroid dysfunction

Different excess-versus-deficiency phenotypes

Slide 67 · Primary reading and source boundaries

CORE TEXTBOOK

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th edition (2026). Peripheral Nerves and Skeletal Muscles.

Main section: “Toxic Myopathies and Myopathy With Metabolic Changes.”

Related source context: “Myopathic Changes,” “Immune-Mediated Necrotizing Myopathy,” and “Mitochondrial Myopathies.”

Illustrations in this presentation are original native PowerPoint schematics; no synthetic diagnostic specimens are shown.