Disorders of metabolism and homeostasis

Metabolic disorders may be congenital or acquired. Congenital metabolic disorders usually result from inherited enzyme deficiencies causing significant clinical consequences. Acquired metabolic disorders are often characterised by perturbations of the body's homeostatic mechanisms that normally maintain the integrity of fluids and tissues. The effect of acquired metabolic disorders is often diverse.

Inborn Errors of Metabolism

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Single-gene defects due to inherited or spontaneous mutations
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Usually manifested in infancy or childhood
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May result in: defective carbohydrate or amino acid metabolism; pathological effects of an intermediate metabolite; impaired membrane transport; synthesis of a defective protein

The concept of inborn errors of metabolism was formulated by Sir Archibald Garrod in 1908 as a result of his studies on a condition called alkaptonuria, a rare inherited deficiency of homogentisic acid oxidase.

Inherited errors of metabolism are an important consideration in differential diagnosis of illness presenting in infancy. Many are potentially fatal early in life or require prompt treatment to avoid serious complications. Others defy treatment. All deserve accurate diagnosis so that parents can be counselled about the causes of the illness and inherent risk to further pregnancies.

There are now pilot schemes where the most common forms of inborn errors of metabolism are now screened for within a few days of birth. If successfully treated, the inborn metabolic errors are potentially chronic problems that may require lifelong treatment or rapid acute intervention at the times of illness. It should be remembered that the primary abnormality is innate rather than due to any external cause that could be eliminated by treatment.

Inborn errors of metabolism are usually single-gene defects resulting in the absence or deficiency of an enzyme or the synthesis of a defective protein. Single-gene defects occur in about 1% of all births, but the diseases caused by them show geographic variations in incidence. This is exemplified by the high incidence of thalassaemias in Mediterranean regions due to defects in haemoglobin synthesis making the red blood cells, and hence individuals, less susceptible to malaria ( Ch. 23 ). These variations reflect the external influences on the prevalence of specific abnormal genes in different populations.

Inborn errors of metabolism have four possible consequences:

accumulation of an intermediate metabolite (e.g. homogentisic acid in alkaptonuria)
deficiency of the ultimate product of metabolism (e.g. melanin in albinos)
synthesis of an abnormal and less effective end-product (e.g. haemoglobin S in sickle cell anaemia)
failure of transport of the abnormal synthesised product (e.g. alpha-1 antitrypsin deficiency).

Accumulation of an intermediate metabolite may direct toxic or hormonal effects. However, in some conditions the intermediate metabolite accumulates within the cells in which it has been synthesised, causing them to enlarge and compromising their function or that of neighbouring cells; these conditions are referred to as storage disorders (e.g. Gaucher disease). Other inborn metabolic errors lead to the production of a protein with defective function; for example, the substitution of just a single amino acid in a large protein can have considerable adverse effects (e.g. haemoglobinopathies).

The genetic basis of the inheritance of these disorders is discussed in Chapter 3 .

Inherited metabolic disorders may be classified according to the principal biochemical defect (e.g. amino acid disorder) or the consequence (e.g. storage disorder).

Disorders of carbohydrate metabolism

Although disease processes such as diabetes mellitus have some inherited component (likely due to human leucocyte antigen associations), those which are pure inherited disorders with an autosomal recessive pattern of inheritance and often presenting at an early age are:

glycogen storage disease , in which the principal effects are due to the intracellular accumulation of glycogen and inability to release glucose from glycogen
fructose intolerance , in which liver damage results from a deficiency of fructose-1-phosphate aldolase
galactosaemia , in which damage to the liver occurs due to a deficiency of galactose-1-phosphate uridyl transferase
tyrosinaemia , in which liver damage and, in chronic cases, liver cell carcinoma results from a deficiency of fumarylacetoacetate hydrolase.

Disorders of amino acid metabolism

Several inherited disorders of amino acid metabolism involve defects of enzymes in the phenylalanine/tyrosine pathway ( Fig. 6.1 ).

Fig. 6.1, Inborn errors of metabolism in the phenylalanine/tyrosine pathway.

Phenylketonuria

This autosomal recessive disorder affects approximately 1 in 10,000 infants. Almost all cases are due to a deficiency of phenylalanine hydroxylase , an enzyme responsible for the conversion of phenylalanine to tyrosine (see Fig. 6.1 ).

The clinical effects of phenylketonuria are now seen only very rarely in Western cultures. This is due to bloodspot (Guthrie) screening of all newborn infants and prompt treatment. If phenylketonuria is not tested for in this way and the affected infant's diet contains usual amounts of phenylalanine, the disorder manifests itself with skin and hair depigmentation, fits and mental retardation. Successful treatment involves a low phenylalanine diet until the teenage years. If affected females become pregnant, the special diet must be resumed to avoid the toxic metabolites damaging the developing fetus.

Alkaptonuria

This rare autosomal recessive deficiency of homogentisic acid oxidase (see Fig. 6.1 ) is an example of an inborn metabolic error that does not produce serious effects until adult life. Classically, the patient's urine darkens on standing and the sweat may also be black! Homogentisic acid accumulates in connective tissues, principally cartilage, where the darkening is called ochronosis . This accumulation causes joint damage. The underlying condition cannot be cured; treatment is symptomatic only.

Homocystinuria

Homocystinuria is an autosomal recessive disorder. It is due to a deficiency of cystathionine synthase (see Fig. 6.1 ). Homocysteine and methionine, its precursor, accumulate in the blood. Homocysteine also accumulates, interfering with the cross-linking of collagen and elastic fibres. The disease resembles Marfan syndrome but mental retardation and fits may also be present.

There is an association with moderately raised homocysteine and early onset of atherosclerosis, but this association has yet to lead to active measurement or treatment in routine practice.

Storage disorders

Inborn metabolic defects result in storage disorders if a deficiency of an enzyme, usually lysosomal, prevents the normal conversion of a macromolecule (e.g. glycogen) into its smaller subunits (e.g. glucose). The macromolecule accumulates within the cells that normally harbour it, swelling their cytoplasm ( Fig. 6.2 ) and causing organ enlargement and deformities. This impairs function in the cell or of its immediate neighbours due to pressure effects. There may also be conditions resulting from deficiency of the smaller subunits (e.g. hypoglycaemia in the case of glycogen storage disorders).

Fig. 6.2, Bone marrow biopsy revealing Gaucher disease.

The major categories of these autosomal recessive disorders are described in Table 6.1 .

Table 6.1

Examples of inborn errors of metabolism resulting in storage disorders

Type of disease/examples	Deficiency	Consequences
Glycogenoses	Debranching enzyme	Hepatomegaly
		Hypoglycaemia
		Cardiac failure
		Muscle cramps
McCardle syndrome	Muscle phosphorylase
von Gierke disease	Glucose-6-phosphate dehydrogenase
Pompe disease	Acid maltase
Mucopolysaccharidoses	Lysosomal hydrolase	Hepatosplenomegaly
		Skeletal deformity
		Mental deterioration
Hurler syndrome	Alpha-L-iduronidase
Hunter syndrome	Iduronate sulphate sulphatase
Sphingolipidoses	Lysosomal enzyme	Variable hepatosplenomegaly
Sphingolipidoses	Lysosomal enzyme	Neurological problems
Gaucher disease	Glucocerebrosidase
Niemann–Pick disease	Sphingomyelinase
Tay–Sachs disease	Hexosaminidase A

Disorders of cell membrane transport

Inborn metabolic errors can lead to impairment of the specific transport of substances across cell membranes.

Examples include:

cystic fibrosis : a channelopathy (see below) affecting exocrine secretions
cystinuria : affecting renal tubules and resulting in renal stones
disaccharidase deficiency : preventing absorption of lactose, maltose and sucrose from the gut
nephrogenic diabetes insipidus : due to insensitivity of renal tubules to antidiuretic hormone (ADH).

Channelopathies

A channelopathy is caused by the dysfunction of a specific ion channel in cell membranes. Ion channel dysfunction may result from:

mutations, usually inherited, in the genes encoding proteins involved in transmembrane ionic flow (e.g. cystic fibrosis)
autoimmune injury to ion channels in cell membranes (e.g. myasthenia gravis).

Cystic fibrosis

This channelopathy is the commonest serious inherited metabolic disorder in the UK; it is much more common in Caucasians. The autosomal recessive abnormal gene is carried by approximately 1 in 20 Caucasians with the condition affecting approximately 1 in 2000 births. The defective gene, in which numerous mutations have been identified, is on chromosome 7 and ultimately results in abnormal water and electrolyte transport across cell membranes.

Cystic fibrosis transmembrane conductance regulator

The commonest abnormality (ΔF508) in the cystic fibrosis transmembrane regulator ( CFTR) gene is a deletion resulting in a missing phenylalanine. The defective CFTR molecule is unresponsive to cyclic adenosine monophosphate control, so transport of chloride ions and water across epithelial cell membranes becomes impaired ( Fig. 6.3 ).

Fig. 6.3, Defective chloride secretion in cystic fibrosis.

Clinicopathological features

Cystic fibrosis is characterised by mucous secretions of abnormally high viscosity. The abnormal mucus plugs exocrine ducts, causing parenchymal damage to the affected organs. The clinical manifestations are:

meconium ileus in neonates
failure to thrive in infancy
recurrent bronchopulmonary infections, particularly with Pseudomonas aeruginosa
bronchiectasis
chronic pancreatitis, sometimes accompanied by diabetes mellitus due to islet damage
malabsorption due to defective pancreatic secretions
infertility in males.

Diagnosis

Although at-risk pregnancies can be screened by prenatal testing of chorionic villus biopsy tissue for the defective CFTR gene, there is now a growing neonatal screening programme using blood spot immunoreactive trypsinogen. The diagnosis can be confirmed in children by measuring the chloride concentration in the sweat; in affected children, it is usually greater than 60 mmol/L.

Treatment

Treatment includes vigorous physiotherapy to drain the abnormal secretions from the respiratory passages, and oral replacement of pancreatic enzymes.

Porphyrias

Porphyria occurs due to defective synthesis of haem, an iron–porphyrin complex, the oxygen-carrying moiety of haemoglobin. Haem is synthesised from 5-aminolaevulinic acid. The different types of porphyrin accumulate due to inherited defects in this synthetic pathway ( Fig. 6.4 ). All forms of porphyria may be acquired as autosomal dominant disorders, although 80% of porphyria cutanea tarda, the commonest chronic porphyria, are associated with risk factors such as haemochromatosis, certain polymorphisms in cytochromes (CYP1A2) and the transferring receptor 1 gene mutations, hepatitis C and HIV infections, excess alcohol intake, and exposure to oestrogens in women.

Clinicopathological features

In acute intermittent porphyria, accumulation of porphyrins can cause clinical syndromes related to both autonomic and motor neuropathies. These are characterised by:

acute abdominal pain
acute psychiatric disturbance
peripheral neuropathy.

The pain and psychiatric disturbances are episodic. During the acute attacks of acute intermittent porphyria, the patient's urine contains excess 5-aminolaevulinic acid and porphobilinogen. Classically, the urine may gradually become dark red, brown or even purple (‘porphyria’ is derived from the Greek word ‘porphura’ meaning purple pigment) on exposure to sunlight.

Attacks of acute intermittent porphyria can be precipitated by some drugs, alcohol and hormonal changes (e.g. during the menstrual cycle). The most frequently incriminated drugs include barbiturates, sulphonamides, oral contraceptives and anticonvulsants; these should therefore be avoided.

The chronic porphyrias may lead to:

photosensitivity (in some porphyrias only)
hepatic damage (in some porphyrias only).

The skin lesions are characterised by severe blistering, exacerbated by light exposure, and subsequent scarring. This photosensitivity is a distressing feature, but it has led to the beneficial use of injected porphyrins in the treatment of tumours by phototherapy with laser light.

Disorders of connective tissue metabolism

Most inherited disorders of connective tissue metabolism affect collagen or elastic tissue. Examples include:

osteogenesis imperfecta
Marfan syndrome
Ehlers–Danlos syndrome
pseudoxanthoma elasticum
cutis laxa.

Osteogenesis imperfecta

Osteogenesis imperfecta is a group of disorders in which there is an inborn error of type I collagen synthesis ( Ch. 25 ). It occurs in both dominantly and recessively inherited forms with varying severity. Type I collagen is most abundant in bone. The principal manifestation is skeletal weakness resulting in deformities and a susceptibility to fractures. The teeth are also affected and the sclerae of the eyes are abnormally thin, causing them to appear blue.

Marfan syndrome

Marfan syndrome is a combination of unusually tall stature, long arm span, dislocation of the lenses of the eyes, aortic and mitral valve incompetence, and weakness of the aortic media predisposing to dissecting aneurysms ( Ch. 13 ). The condition results from a defect in the FBN1 gene encoding for fibrillin , a glycoprotein essential for the formation and integrity of elastic fibres.

Acquired Metabolic Disorders

Many diseases result in secondary metabolic abnormalities. In others, the metabolic disturbance is the primary event. For example, renal diseases almost always result in metabolic changes that reflect the kidneys' importance in water and electrolyte homeostasis. In contrast, a disease such as gout is often due to a primary metabolic disorder that may secondarily damage the kidneys. This section deals with metabolic abnormalities as both consequences and causes of disease. Acquired metabolic disorders frequently cause systemic problems affecting many organs.

Disorders such as diabetes mellitus and gout are categorised as ‘acquired’ largely because they occur most commonly in adults, but both have a significant genetic component in their aetiology. Diabetes mellitus is covered in detail in Chapter 17 but an overview of gout may be used as a paradigm for such disorders.

Gout

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Multifactorial disorder characterised by high blood uric acid levels
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Urate crystal deposition causes skin nodules (tophi), joint damage, renal damage and stones

Gout is a common disorder resulting from high blood uric acid levels. Uric acid is primarily a breakdown product of the body's purine (nucleic acid) metabolism ( Fig. 6.5 ). Uric acid is excreted by the kidneys. Blood uric acid is primarily in the form of monosodium urate. In patients with gout, the high monosodium urate concentration creates a supersaturated solution, thus risking urate crystal deposition in tissues causing:

tophi (subcutaneous nodular deposits of urate crystals)
synovitis and arthritis ( Ch. 25 )
renal disease and calculi ( Ch. 21 ).

Gout occurs more commonly in men, and is rare before puberty. A rare form of gout in children — Lesch–Nyhan syndrome — is due to absence of the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT) (see Fig. 6.5 ) and is associated with mental deficiency and a bizarre tendency to self-mutilation.

Aetiology

The aetiology of gout is multifactorial. There is a genetic component, but the role of other factors justifies the inclusion of gout under the heading of acquired disorders. These include:

gender (male > female)
family history
diet (meat, alcohol)
socioeconomic status (high > low)
body size (obesity).

Some of these factors are interdependent. Accordingly, gout can be subdivided into primary gout , due to some genetic abnormality of purine metabolism, or secondary gout , due to increased liberation of nucleic acids from necrotic tissue or decreased urinary excretion of uric acid.

Clinicopathological features

The clinical features of gout are due to urate crystal deposition ( Fig. 6.6 ). In joints, a painful acute arthritis results from phagocytosis of the crystals by neutrophil polymorphs, in turn causing release of lysosomal enzymes along with the indigestible crystals, thus accelerating and perpetuating a cyclical inflammatory reaction. The first metatarsophalangeal joint is typically affected.

Fig. 6.6, Histology of urate crystal deposition in gout.

Water homeostasis

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Abnormal water homeostasis may result in excess, depletion or redistribution
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Excess may be due to overload, oedema or inappropriate renal tubular reabsorption
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Dehydration is most commonly due to gastrointestinal loss (e.g. gastroenteritis)
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Oedema results from redistribution of water into the extravascular compartment

Water (and hence electrolyte homeostasis) is tightly controlled by various hormones, including ADH, aldosterone and natriuretic peptides, acting upon selective reabsorption in the renal tubules ( Ch. 21 ). The process is influenced by the dietary intake of water and electrolytes (in food or drinking in response to thirst or social purposes) and the adjustments necessary to cope with disease or adverse environmental conditions.

Many diseases result in problems of water and electrolyte homeostasis. Disturbances also occur in patients receiving fluids and nutrition parenterally. Any changes are easy to monitor via biochemical tests and control by making adjustments to the fluid and electrolyte intake.

Water is constantly lost from the body — in urine, faeces, exhaled gas from the lungs, and from the skin. The replenishment of body water is controlled by a combination of the satisfaction of the sensation of thirst and the regulation of the renal tubular reabsorption of water mediated by ADH.

Dehydration

Dehydration results from either excessive water loss, inadequate intake or a combination of both. Inadequate water intake may be due to environmental drought or, again, due to poor fluid management in hospital patients.

Excessive water loss can be due to:

vomiting and diarrhoea
extensive burns
excessive sweating (fever, exercise, hot climates)
diabetes insipidus (failure to produce ADH)
nephrogenic diabetes insipidus (renal tubular insensitivity to ADH)
diuresis (e.g. osmotic loss accompanying the glycosuria of diabetes mellitus).

Clinical signs may include a dry mouth, inelastic skin and, in extreme cases, sunken eyes. The blood haematocrit (proportion of the blood volume occupied by cells) will be elevated. This results in an increase in whole blood viscosity, causing a sluggish circulation and consequent impairment of the function of many organs.

The blood sodium and urea concentrations are typically elevated, reflecting haemoconcentration and impaired renal function.

Water excess

Excessive total body water occurs in patients with oedema or if there is inappropriate production of ADH (e.g. as occurs with small-cell lung carcinoma) or if the body sodium concentration increases due to excessive tubular reabsorption (e.g. due to an aldosterone-secreting tumour of the adrenal cortex). Water overload may also occur with excessive parenteral infusion of fluids in patients with impaired renal function, hence requiring careful fluid balance monitoring.

Oedema and serous effusions

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Oedema is excess water in tissues
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Oedema and serous effusions have similar pathogeneses
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May be due to increased vascular permeability, venous or lymphatic obstruction, or reduced plasma oncotic pressure.

Oedema is an excess of fluid in the intercellular compartment of a tissue. A serous effusion is an excess of fluid in a serous or coelomic cavity (e.g. peritoneal cavity or pleural cavity). The main ingredient of the fluid is always water . Oedema and serous effusions share common mechanisms.

Oedema is recognised clinically by diffuse swelling of the affected tissue. If the oedema is subcutaneous, there may be pitting. Oedema of internal tissues may be evident during surgery. They may be swollen and, when incised, clear or slightly opalescent fluid oozes from the cut surfaces. Pulmonary oedema gives a characteristic radiopacity on a plain chest x-ray and can be heard as crepitations on auscultation.

Oedema may have serious consequences. In pulmonary oedema , fluid fills the alveoli and reduces the effective lung volume available for respiration, causing breathlessness (dyspnoea) and cyanosis. Cerebral oedema is an ominous development because it occurs within the rigid confines of the cranial cavity; compression of the brain against the falx cerebri, the tentorial membranes or the base of the skull leads to herniation of brain tissue, possibly causing irreversible and fatal damage. Papilloedema (oedema of the optic disc) may be observed with ophthalmoscopy.

Oedema and serous effusions are due to:

excessive leakage of fluid from blood vessels into the extravascular spaces
impaired reabsorption of fluid from tissues or serous cavities.

Oedema is classified into four pathogenetic categories ( Fig. 6.7 ):

inflammatory: due to increased vascular permeability
venous: due to increased intravenous pressure
lymphatic: due to obstruction of lymphatic drainage
hypoalbuminaemic: due to reduced plasma oncotic pressure.

Serous effusions can be attributable to any of the above causes, but in addition neoplastic effusions due to primary or secondary neoplasms (tumours) involving serous cavities ( Ch. 10 ).

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