of metabolism and homeostasis

Chapter 7 Disorders of metabolism and homeostasis



Some metabolic disorders, congenital or acquired, are specific abnormalities of metabolic pathways, often having considerable clinical effects. Congenital metabolic disorders usually result from inherited enzyme deficiencies.


Other metabolic disorders are characterised by perturbations of the body’s homeostatic mechanisms maintaining the integrity of fluids and tissues. These conditions are almost always acquired and their effects can be diverse.



INBORN ERRORS OF METABOLISM




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.


Inborn (usually inherited) errors of metabolism are important causes of illness presenting in infancy. Some require prompt treatment to avoid serious complications. Others defy treatment. All deserve accurate diagnosis so that parents can be counselled about the inherited risk to further pregnancies. Inborn metabolic errors are potentially chronic problems, because the primary abnormality is innate rather than due to any external cause that could be eliminated by treatment.


Inborn errors of metabolism are 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—due to defects in haemoglobin synthesis (Ch. 23)—in Mediterranean regions. These variations reflect the prevalence of specific abnormal genes in different populations.


Inborn errors of metabolism have four possible consequences:






Accumulation of an intermediate metabolite may have 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’s 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 amino acid metabolism


Several inherited disorders of amino acid metabolism involve defects of enzymes in the phenylalanine/tyrosine pathway (Fig. 7.1).





Alkaptonuria


This rare autosomal recessive deficiency of homogentisic acid oxidase (Fig. 7.1) is a good example of an inborn metabolic error that does not produce serious effects until adult life. The condition is sometimes recognised from the observation that the patient’s urine darkens on standing; 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.




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 or gangliosides) into its smaller subunits (e.g. glucose or fatty acids). The macromolecule accumulates within the cells that normally harbour it, swelling their cytoplasm (Fig. 7.2) and causing organ enlargement and deformities. This situation is harmful to the patient because the swelling of cells often impairs their function, or that of their immediate neighbours due to pressure effects, and because of conditions resulting from deficiency of the smaller subunits (e.g. hypoglycaemia in the case of glycogen storage disorders).



Major categories of these autosomal recessive disorders (Table 7.1) are:





Table 7.1 Examples of inborn errors of metabolism resulting in storage disorders



















































Type of disease/examples Deficiency Consequences
Glycogenoses Debranching enzyme



McCardle’s syndrome Muscle phosphorylase  
von Gierke’s disease Glucose-6-phosphate dehydrogenase  
Pompe’s disease Acid maltase  
Mucopolysaccharidoses Lysosomal hydrolase


Hurler’s syndrome Alpha-l-iduronidase  
Hunter’s syndrome Iduronate sulphate sulphatase  
Sphingolipidoses Lysosomal enzyme

Gaucher’s disease Glucocerebrosidase  
Niemann–Pick disease Sphingomyelinase  
Tay–Sachs disease Hexosaminidase A  



Channelopathies


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





Cystic fibrosis


Cystic fibrosis, a channelopathy, is the commonest serious inherited metabolic disorder in the UK; it is much commoner in Caucasians than in other races. The autosomal recessive abnormal gene is carried by approximately 1 in 20 Caucasians and the condition affects 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.







Porphyrias


The porphyrias, transmitted as autosomal dominant disorders, are 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. 7.4).





Disorders of connective tissue metabolism


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








Osteogenesis imperfecta


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




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 like 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: for example, diabetes mellitus is associated with microvascular damage in the retinas, nerves, kidneys and other organs; electrolyte imbalance compromises the function of cells in all tissues.


Two of the disorders discussed in this section—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




Diabetes mellitus is a group of diseases characterised by impaired glucose homeostasis resulting from a relative or absolute insufficiency of insulin. Insulin insufficiency causes hyperglycaemia and glycosuria. Diabetes is covered in Chapter 17, but a brief account is relevant here.


The aetiology is multifactorial; although the disorder is acquired, there is a significant genetic predisposition. Diabetes mellitus is subclassified into primary and secondary types. Primary diabetes is much more common than diabetes secondary to other diseases.






Gout




Gout is a common disorder resulting from high blood uric acid levels. Uric acid is a breakdown product of the body’s purine (nucleic acid) metabolism (Fig. 7.5), but a small proportion comes from the diet. Most uric acid is excreted by the kidneys. In the blood, most uric acid is in the form of monosodium urate. In patients with gout, the monosodium urate concentration may be very high, forming a supersaturated solution, thus risking urate crystal deposition in tissues causing:






Gout occurs more commonly in men than in women, and is rare before puberty. A rare form of gout in children—Lesch–Nyhan syndrome—is due to absence of the enzyme HGPRT (hypoxanthine guanine phosphoribosyl transferase) (Fig. 7.5) and is associated with mental deficiency and a bizarre tendency to self-mutilation.





Water homeostasis




Water and electrolyte homeostasis is tightly controlled by various hormones, including antidiuretic hormone (ADH), aldosterone and atrial natriuretic peptide, 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 can also occur in post-operative patients receiving fluids and nutrition parenterally. Fortunately, any changes are fairly easy to monitor and control by making adjustments to the fluid and electrolyte intake.


Water is constantly lost from the body—in urine, in faeces, in 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.




Jun 16, 2017 | Posted by in GENERAL SURGERY | Comments Off on of metabolism and homeostasis

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