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
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