METABOLIC DISEASE PATHOLOGY

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CHAPTER 15 METABOLIC DISEASE PATHOLOGY

Approach to metabolic disease pathology
Organic acidemias
Disorders of amino acid metabolism
Urea cycle defects
Fatty acid oxidation disorders
Lactic acidemias
Disorders of carbohydrate metabolism
Peroxisomal disorders
Purine metabolism disorders
Transport pathway disorders
Mucopolysaccharidoses
Mucolipidoses
Lipid storage disorders
Batten disease (neuronal ceroid lipofuscinosis)

APPROACH TO METABOLIC DISEASE PATHOLOGY

Overview (Nyhan et al 2005)

• Metabolic disease can have a wide range of clinical presentation throughout the pediatric age range

image often in early life
image mixture of

– neuromuscular disorders
– failure to thrive
– acute exacerbations

· may be precipitated by infections

• Definitive diagnosis is often based on clinical, biochemical, genetic and pathological findings

image often specific biochemical and enzymological tests

– require blood and/or fresh tissue
– enzyme analysis of fibroblast cultures

• Many disorders have non-specific histological features
• Surgical pathology samples are not part of routine investigation for most metabolic diseases

image encountered mainly in the following settings:

– for primary diagnosis of metabolic disease

· rare

– for further investigation of suspected disease

· often bone marrow or liver biopsy

image screening for metabolic disease

– see chapter 19 regarding hair and blood samples

image other indications

– incidental in patients with metabolic disease

• Many disorders are discussed in the appropriate organ-specific chapters
• This chapter provides only the main features relevant to a diagnostic histopathologist who encounters a surgical pathology specimen in a child with suspected metabolic disease

image full details of biochemical and genetic findings are not included
image autopsy findings are not included

– only included here are samples which may be encountered in surgical pathology practice

ORGANIC ACIDEMIAS

• Present with metabolic acidemia / aciduria

image many with lactic acidemia

• Variety of pathways affected
• Rarely associated with specific histopathological features
• Methymalonic acidemia

image hepatomegaly
image non-specific tubulointerstitial nephritis

DISORDERS OF AMINO ACID METABOLISM

• Most do not have characteristic histological findings

image present with mental retardation and other features

• Tyrosinemia (fumarylacetoacetate hydrolase deficiency)

image infantile cirrhosis (see liver chapter; Prive 1967, Carson et al 1976, Russo 1990)

– development of hepatocellular carcinoma
image may develop hypertrophic cardiomyopathy

UREA CYCLE DEFECTS

• Most present with neonatal coma

image hyperammonemia

• Liver biopsy and enzyme analysis may be carried out

image non-specific morphological features

• Argininosuccinic aciduria

image trichorrhexis nodosa
image hepatomegaly

• Lysinuric protein intolerance

image diarrhea with villous atrophy
image acrodermatitis

– may resemble celiac disease clinically

image some show bone marrow changes

– sea-blue histiocyte-like cells
– erythrophagocytosis

image lung pathology

– interstitial fibrosis
– cholesterol crystals / granulomas

image liver pathology

– normal
– variable fatty change
– cirrhosis

FATTY ACID OXIDATION DISORDERS

• Diagnosis by tandem mass spectrometry and biochemical / enzyme and genetic confirmation
• Variable presentation:

image sudden infant death
image cardiomyopathy
image Reye-like syndrome

• Non-specific histological findings

image liver biopsy shows microvesicular and/or macrovesicular
image muscle biopsy is either normal or shows fat accumulation

• Electron microscopy

image liver and/or muscle fat accumulation
image may show abnormal mitochondria and peroxisomes

• Multiple acyl CoA dehydrogenase deficiency (Glutaric aciduria type II)

image as above
image syndromic type polycystic kidneys
image cortical dysplasias and heterotopias

LACTIC ACIDEMIAS

• Complex group
• Lactic acidemia may be secondary to other metabolic disorders

image especially with intercurrent stress or infection

• Primary lactic acidemias disorders of pyruvate metabolism
• Some due to nuclear or mitochondrial DNA defects
• Some no identifiable cause
• Variable presentations:

image acute lactic acidosis
image ataxia
image myopathy
image Leigh syndrome (subacute necrotizing encephalomyelopathy)

– autopsy diagnosis

• Variability in part due to heteroplasmy in mitochondrial diseases
• Muscle biopsy may be performed

image morphology
image mitochondrial structure / function
image DNA extraction

• In addition to these features specific histological findings include:

image myoclonic epilepsy and ragged red fibers

– multiple lipomas neck / trunk

image Pearson syndrome

– infantile anemia and pancytopenia

· hypercellular marrow
· vacuolated precursors
· ring sideroblasts

image mitochondrial depletion syndromes

– cirrhosis, cholestasis, steatosis, hemosiderosis
– pleomorphic mitochondria on electron microscopy:

· Alpers’ syndrome:
· neurological symptoms
· episodes of decompensation
· liver changes as above
· additional neuropathological changes (autopsy)

DISORDERS OF CARBOHYDRATE METABOLISM

• Galactosemia

image vomiting, jaundice, hepatomegaly, FTT, cataracts, mental retardation

– may present with E. coli neonatal sepsis

image histological specimens most often liver biopsy (see chapter 10)

• Glycogen storage diseases

image group characterized by abnormal metabolism of glycogen and

– deposition of glycogen in tissues
– hypoglycemia and ketosis (variable)

image histological specimens most often liver biopsy (see chapter 10)
image Type I – Von Gierke Disease

– neonatal liver biopsy may be normal
– hepatic adenomas may develop

image Type II – Pompe

– lysosomal storage disease with alpha-glucosidase deficiency

· membrane bound lysosomal glycogen storage

– cardiomyopathy with cardiomegaly
– skeletal myopathy
– vacuolated lymphocytes (Figs 15.1, 15.2) (see chapter 10)

image Type III – debrancher deficiency

– hepatomegaly
– myopathy

image

Fig 15.1 Photomicrograph of blood film showing lymphocyte vacuolation in Pompe disease.

image

Fig 15.2 Photomicrograph of blood film showing lymphocyte vacuolation in Pompe disease. (PAS)

PEROXISOMAL DISORDERS

(Roels et al 1991, 1993, Dimmick et al 1993, Powers 1995)

• Neonatal adrenoleukodystrophy
• Zellweger
• Many others now recognized
• Present with:

image hypotonia
image seizures

• Liver biopsy

image periportal fibrosis
image PAS + macrophages
image absent or reduced peroxisomes on EM

• Adrenals

image cortical atrophy
image ballooning degeneration

– lipid-rich cells

PURINE METABOLISM DISORDERS

• Lesch–Nyhan

image urate nephropathy
image early onset gout

• APRT deficiency

image calculi and crystalluria

• PRPP synthetase deficiency

image calculi, crystalluria
image early onset gout

• ADA deficiency (see immunodeficiencies)

TRANSPORT PATHWAY DISORDERS

• Cystinuria

image cystine calculi

– recurrent urinary infections
– chronic renal damage

• Cystinosis

image renal Fanconi syndrome in infancy
image calculi
image nephrocalcinosis
image cystine nephropathy
image cystine crystals identified in tissues

– renal biopsy
– bone marrow trephine biopsy
– conjunctival biopsy

• Menkes’ disease

image defective copper transport mechanisms (ATP7A)
image pili torti (see hair – chapter 19)
image widespread vasculopathy

– defective elastic laminae
– areas of narrowing and dilatation

· may have superimposed thrombi

image urinary and gastrointestinal diverticulae

• Wilson disease

image defective copper transport mechanisms

– specific to liver (ATP7B)

image liver and neurological disease (see chapter 10)
image measurement of copper levels in liver biopsy is diagnostic

MUCOPOLYSACCHARIDOSES

• Abnormal glycosaminoglycan storage in tissues due to defective normal degradation processes

image vacuolated cells in liver, spleen and marrow ± other

– esp chondrocytes

image may be detectable ultrastructurally

• Characteristic phenotypes for each disease

image often coarse facies

• Bony defects

image dysostosis multiplex

• Hepatosplenomegaly (see chapter 10)
• Cardiac complications

image cardiomyopathy
image valvular disease
image coronary angiopathy

• Specific histological features include:

image Hurler disease

– vacuolated cells in liver, spleen and marrow
– Reilly bodies in leukocytes, inc macrophages

· granular inclusions

image Maroteaux–Lamy disease

– prominent cytoplasmic inclusions

· metachromatic in granulocytes

MUCOLIPIDOSES

• Clinically similar to mucopolysacchardidoses
• Widespread abnormal vacuolation

image acid phosphatase +
image sudanophilic

LIPID STORAGE DISORDERS

• Fabry disease (Sessa et al 2001, Elleder 2003, Linthorst et al 2004)

image usually only angiokeratomas in adolescence

– renal disease occurs in adulthood

image electron microscopy shows endothelial cells with lamellar lysosomal inclusions (Figs 15.3, 15.4)
• GM1 gangliosidosis

image may present in infancy

– rarely even with fetal hydrops

image hepatomegaly

– inclusions in hepatocytes and Kupffer cells

image ballooning cytoplasmic vacuolation of glomerular epithelium
image vacuolated lymphocytes may be present (Fig 15.5)

• Tay–Sachs

image minimal systemic accumulation of storage material

– mainly CNS neuronal ballooning

• GM2 gangliosidosis

image presents as Tay–Sachs

– visceral lipid laden macrophages also

• Gaucher disease (Parkin et al 1982, Bove et al 1995, Jmoudiak et al 2005)

image hepatosplenomegaly (see chapter 10)
image characteristic Gaucher cells in bone marrow or liver/spleen (Figs 15.6–15.8)

– large lipid-laden macrophages
– foamy and fibrillary cytoplasm
• Niemann–Pick disease (Kuemmel et al 1997, Ikonen et al 2004)

image Types A & B (Fig 15.9)

– may present in infancy

· rarely with fetal hydrops

– hepatosplenomegaly
– may have pulmonary infiltrates
– characteristic abnormal foamy storage macrophages (foam cell)

· numerous uniform lipid droplets
· sea-blue on Wright stain
· membrane bound lucencies on EM

image Type C (Figs 15.10–15.14)

– usually present later
– foam cells
• Wolman disease (Figs 15.15–15.17) (Boldrini et al 2004)

image characteristic adrenal calcification
image vacuolated lymphocytes and granulocytes may be present
image foam cells on bone marrow aspirates
image vacuolated hepatocytes and Kupffer cells
• Fucosidosis

image vacuolated lymphocytes
image hepatosplenomegaly

– foamy cells in bone marrow and liver biopsy

• Alpha-mannosidosis

image vacuolated lymphocytes
image hepatosplenomegaly

– foamy cells in bone marrow and liver biopsy

• Galactosialidosis

image may present with fetal hydrops
image hepatosplenomegaly
image dysostosis multiplex
image cardiomegaly

– foamy cells in bone marrow and liver biopsy

• Metachromatic leukodystrophy (Figs 15.18–15.20)

image inclusion bodies in peripheral nerve biopsies (see muscle and nerve chapter)
image

Fig 15.3 Electron photomicrograph of a renal biopsy showing numerous lamellar lysosomal inclusions in Fabry disease.

image

Fig 15.4 Photomicrograph of urine showing a ‘mulberry cell’ in Fabry disease. (PAS)

image

Fig 15.5 Photomicrograph of blood film showing coarse lymphocyte vacuolation in GM1 gangliosidosis.

image

Fig 15.6 Photomicrograph of bone marrow aspirate showing large lipid laden macrophages with fibrillary cytoplasm in Gaucher disease.

image

Fig 15.7 Photomicrograph of splenic biopsy showing large lipid laden macrophages with fibrillary cytoplasm in Gaucher disease.

image

Fig 15.8 Electron photomicrograph of a Gaucher cell demonstrating membrane bound tubular inclusions in Gaucher disease.

image

Fig 15.9 Photomicrograph of bone marrow aspirate showing macrophages with numerous uniform small vacuoles and no particles Niemann–Pick type A.

image

Fig 15.10 Photomicrograph of bone marrow aspirate showing macrophages with numerous variably sized vacuoles and particulate matter in Niemann–Pick type C.

image

Fig 15.11 Photomicrograph of bone marrow aspirate showing macrophages with numerous variably sized vacuoles in Niemann–Pick type C. (PAS)

image

Fig 15.12 Photomicrograph of bone marrow aspirate showing sea-blue histiocytes in Niemann–Pick type C. (MGG)

image

Fig. 15.13

image

Figs 15.13–15.14 Photomicrographs of bone marrow aspirates showing numerous abnormal macrophages with numerous variably sized vacuoles in Niemann–Pick type C. (Alkaline phosphatase)

image

Fig 15.15 Photomicrograph of a liver biopsy showing numerous lipid vacuoles, some also containing cholesterol-clefts, in Wolman disease.

image

Fig 15.16 Photomicrograph of a small bowel biopsy showing numerous lipid laden cells in Wolman disease. (Oil Red O)

image

Fig 15.17 Electron photomicrograph of a chorionic villous sample showing membrane bound lipid vacuoles in Wolman disease.

image

Fig 15.18 Photomicrograph of a renal biopsy showing tubular epithelial cells containing brown metachromatic material.

image

Fig. 15.19

image

Figs 15.19–15.20 Photomicrographs of urine showing shed tubular epithelial cells containing brown metachromatic material, with yellow green birefringence on polarization.

BATTEN DISEASE (NEURONAL CEROID LIPOFUSCINOSIS)

• Group of related neurodegenerative diseases (Williams et al 1977, Brod et al 1987, Tyynelä et al 1997)
• Lysosomal storage diseases but:

image material not fully identified
image many enzyme defects not known

• Diagnosis is based on clinical, genetic and histological features

image increasing use of genetic diagnosis
image some subtypes, especially variant forms, require ultrastructural diagnosis

• Four main clinical subtypes

image infantile
image late infantile
image juvenile
image adult

• Many variants now identified
• Genes assigned to clinical subtypes but not always correlation between genotype and phenotype in an individual

image infantile

– CLN1

image late infantile

– CLN2

image juvenile

– CLN3

image adult

– CLN4

image Finnish variant late infantile

– CLN5

image variant late infantile

– CLN6

image juvenile / late infantile variant

– CLN7

image northern epilepsy

– CLN8

image congenital variant

– not known

• Diagnosis based on electron microscopic examination of blood and/or tissue samples inc neurons, smooth muscle and sweat gland epithelium in skin or rectal biopsies (Figs 15.21–15.39)

image identification of characteristic membrane bound ultrastructural inclusions in each subtype

– note that variant types may show ‘overlap’
– most diagnosable on electron microscopy of blood Buffy coat

image infantile

– granular osmophilic deposits (GRODS)

image late infantile

– curvilinear profiles

image juvenile

– fingerprint bodies

· must be distinguished from FP-like crystalloids

– vacuolated lymphocytes also present on blood film

image several subtypes

– rectilinear profiles
– mixed and complex profiles

image

Fig 15.21 Photomicrograph of a brain biopsy showing neuronal inclusions in Batten disease / NCL.

image

Fig 15.22 Photomicrograph of a sweat gland for the diagnosis of Batten disease / NCL, containing endothelial cells, epithelial cells and smooth muscle, all of which should be examined for inclusions. (Tol blue)

image

Fig 15.23 Photomicrograph of a blood film to allow examination for lymphocyte vacuolation.

image

Fig 15.24 Electron photomicrograph of a lymphocyte showing membrane bound granular osmophilic inclusions (GRODs) in a case of infantile Batten disease / NCL.

image

Fig 15.25 Electron photomicrograph of a lymphocyte showing membrane bound granular osmophilic inclusions (GRODs) in a case of infantile Batten disease / NCL.

image

Fig 15.26 Electron photomicrograph of a neuron showing membrane bound granular osmophilic inclusions (GRODs) in a case of infantile Batten disease / NCL.

image

Fig 15.27 Electron photomicrograph of a lymphocyte showing membrane bound curvilinear inclusions in a case of late infantile Batten disease / NCL.

image

Fig 15.28 Electron photomicrograph of a lymphocyte showing membrane bound curvilinear inclusions in a case of late infantile Batten disease / NCL.

image

Fig 15.29 Electron photomicrograph of a sweat gland showing membrane bound curvilinear inclusions in a case of late infantile Batten disease / NCL.

image

Fig 15.30 Electron photomicrograph of a neuron showing membrane bound curvilinear inclusions in a case of late infantile Batten disease / NCL.

image

Fig 15.31 Electron photomicrograph of a neuron showing membrane bound curvilinear inclusions in a case of late infantile Batten disease / NCL.

image

Fig 15.32 Photomicrograph of a blood film showing coarse lymphocyte vacuolation in a case of juvenile Batten disease / NCL.

image

Fig 15.33 Photomicrograph of a blood film showing coarse lymphocyte vacuolation in a case of juvenile Batten disease / NCL. (Tol blue)

image

Fig 15.34 Electron photomicrograph of a lymphocyte showing fingerprint inclusions in a case of juvenile Batten disease / NCL.

image

Fig 15.35 Electron photomicrograph of a lymphocyte showing fingerprint inclusions in a case of juvenile Batten disease / NCL.

image

Fig 15.36 Electron photomicrograph of a lymphocyte showing fingerprint inclusions in a case of juvenile Batten disease / NCL.

image

Fig 15.37 Electron photomicrograph of a lymphocyte showing fingerprint inclusions but no lymphocyte vacuolation in a case of variant Batten disease / NCL.

image

Fig 15.38 Electron photomicrograph of a lymphocyte showing fingerprint inclusions but no lymphocyte vacuolation in a case of variant Batten disease / NCL.

image

Fig 15.39 Electron photomicrograph of a lymphocyte showing fingerprint inclusions but no lymphocyte vacuolation in a case of variant Batten disease / NCL.

CHORIONIC VILLUS SAMPLES

A range of metabolic diseases may also be diagnosed prenatally based on ultrastructural examination of chorionic villus samples (Figs 15.40–15.46)

image

Fig 15.40 Electron photomicrograph of a chorionic villous sample showing an endothelial cell with granular osmophilic deposits (GRODs) in a fetal case of infantile Batten disease / NCL.

image

Fig 15.41 Electron photomicrograph of a chorionic villous sample showing extensive vacuolation of numerous cell types including trophoblast, in a case of sialic acid storage disease.

image

Fig 15.42 Electron photomicrograph of a chorionic villous sample showing extensive vacuolation in a case of sialic acid storage disease.

image

Fig 15.43 Electron photomicrograph of a chorionic villous sample showing extensive vacuolation of endothelial cells in a case of sialic acid storage disease.

image

Fig 15.44 Electron photomicrograph of a case of infantile neuroaxonal storage disease showing an axon with abnormal storage material.

image

Fig 15.45 Photomicrograph of a case of Lafora body disease, showing abnormal discreet inclusions. (PAS)

image

Fig 15.46 Photomicrograph of a case of Lafora body disease, showing abnormal discreet inclusions. (Lugol’s iodine)

REFERENCES

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Linthorst GE, De Rie MA, Tjiam KH, Aerts JM, Dingemans KP, Hollak CE. Misdiagnosis of Fabry disease: importance of biochemical confirmation of clinical or pathological suspicion. Br J Dermatol. 2004;150:575-577.

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