Disease: Metabolic Diseases

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DISEASE: METABOLIC DISEASES. Metabolism may be defined as those changes in liver cells that provide energy for vital processes. "Metabolic diseases" is a term that includes a vast array of genetic disorders whose effects may be exacerbated or ameliorated by diet. Several groups of these are recognizable and treatable.

One group of metabolic diseases is concerned with errors in the body that fail to preserve equilibrium of the water and salts. Dehydration results from excess water loss compared to intake. Normally, this is compensated for by thirst and the subsequent ingestion of water. Diseases result from loss of the thirst mechanism; excessive water is lost with diseases of the kidney or of the pituitary gland (diabetes insipidus). Diseases of the sweat glands may result in excessive loss of salt. Shock due to low salt in the circulation may occur as a normal blood pressure is not maintained.

Cystic fibrosis of the pancreas is a severe metabolic disease caused by an abnormality of a gene on chromosome 7. Infants may be born with obstruction of the intestine, develop severe diarrhea and/or chronic lung disease, or fail to grow properly. At present, treatment includes special easily absorbable formulas, large doses of vitamins, supplements of enzymes that are made in the pancreas, and frequent administration of specific antibiotics to treat or prevent lung infection.

Salt is lost in patients with the genetic disease cystic fibrosis, an error in one aspect of the function of the pancreas. Loss of function or destruction of pancreatic islet cells, another part of the pancreas, causes type 1 diabetes mellitus, one of the severe common metabolic diseases. The islets of the pancreas are the source of insulin, a hormone responsible for the metabolism of sugar. Without insulin, sugar (glucose) rises in the blood and is excreted in the urine together with excessive water and salt (sodium and chloride). Dehydration results in loss of excess sodium (a base or alkali) and results in the tissues becoming acidotic and the body is in "acidosis." Treatment requires administration of fluids and an excess of sodium compared to chloride (chloride functions as an acid in the body). Because insulin functions in fat metabolism, patients with diabetes may develop atherosclerosis, heart disease, and other complications due to abnormal deposition of fat. The amount of carbohydrate, protein, and fat in the diet must be regulated even in those receiving regular amounts of insulin.

In addition to the pancreas, disturbed function of any of the endocrine glands may result in metabolic disease. For example, the pituitary gland secretes growth hormone. Excessive growth hormone results in gigantism and acromegaly (i.e., overgrowth of parts of the body or the whole body, e.g., progressive enlargement of hands, feet, and face). Deficiency of growth hormone results in dwarfism. The thyroid gland secretes thyroxine, a hormone that controls metabolic rate. Excessive thyroxine results in excessive burning of calories, and affected children fail to thrive (Graves's disease). Insufficiency results in hypothyroidism. In the baby, this may be called cretinism (physical shortness and mental deficiency), and in the older child, myxedema (form of inelastic swelling of the connective tissue). If not treated, these children may be mentally retarded and fail to grow properly. The adrenal glands secrete hormones for maintaining blood pressure. Lack of adrenal function may result in shock. The adrenal glands also are important in sugar metabolism and lack of function may result in low blood sugar (hypoglycemia). Abnormalities of the fetal adrenal glands result in abnormalities of the development of the sexual characteristics and in hypotension or low blood pressure. The parathyroid glands are essential for normal bone function and metabolism. Abnormalities may result in a ricketslike syndrome, or in low blood calcium that may cause seizures. Abnormalities of the ovaries or testes result in abnormalities in sexual development. Abnormalities due to endocrine deficiencies may be corrected by replacement hormones. For those with excessive hormone secretion, surgery or treatment with drugs to inhibit the secretion of the hormone may be effective.


Inappropriate vitamin intake also causes metabolic disease. Vitamin A deficiency results in blindness; night blindness is due to lack of a specific metabolic product, rhodopsin, of vitamin A. Excessive vitamin A may result in increased intracranial pressure due to abnormalities of metabolism of cerebral spinal fluid. Thiamine is necessary for carbohydrate metabolism, and lack of thiamine results in beriberi, a very severe disease involving edema and heart failure. Some people with thiamine deficiency develop central nervous system abnormalities. Niacin is necessary for carbohydrate metabolism. Deficiency results in pellagra, a condition marked by diarrhea, abnormal coloration of the skin, central nervous system abnormalities, and death. Pyridoxine, vitamin B6, is necessary for nerve and other functions. Deficiency results in seizures, abnormal sensation in the hands and feet, and anemia. Biotin is necessary for protein and fatty acid metabolism. Deficiency of biotin results in abnormalities of the hair and skin. Deficiency may occur in those who eat significant amounts of raw eggs. Deficiency of folic acid results in anemia. Deficiency in a pregnant woman results in a fetus with abnormalities of the spinal cord (e.g., spina bifida, myelomeningocele). Vitamin B12 deficiency results in abnormalities of nucleotides that are essential for gene replication and transcription. Clinically, vitamin B12 deficiency manifests as pernicious anemia, which, in addition to anemia, includes abnormalities of the central nervous system. Vitamin C (ascorbic acid) is necessary for the metabolism of interstitial (collagen) support substance. Deficiency results in bleeding, bone pain, and scurvy. Vitamin D is necessary for calcium metabolism. Deficiency results in abnormal bone formation and rickets. Deficiency also may result in secondary hypoparathyroidism, low serum calcium, and seizures. Excess may result in abnormal deposition of calcium in the kidneys and brain resulting in kidney failure and brain abnormalities. Vitamin E participates as an antioxidant. Vitamin K functions in clotting mechanism and bone metabolism. Treatment of any of the vitamin deficiencies or excesses requires control of intake, unless due to primary metabolic diseases that may inhibit absorption of the vitamin or its proper metabolism.


Of the sixteen minerals said to be essential to humans, several are of special importance. Sodium, already discussed, is essential for acid-base homeostasis (maintenance of a steady state). Potassium is essential for nerve transmission and its importance is noted in maintaining heart rate regularity. Chloride is essential for water homeostasis and acid-base balance. Low sodium and chloride may result in hypotension, and elevated sodium chloride, in hypertension. Calcium and phosphorus participate in bone metabolism and in nerve transmission. Low serum calcium may result in seizures. Iron and copper are necessary for hemoglobin formation. Copper is also important in protein formation. Iodine is essential for thyroid metabolism. Zinc participates as a cofactor for many of the liver enzymes. Other trace minerals have been suggested as essential elements. Deficiency or excess of any of the minerals may be prevented by appropriate dietary intake unless, like the vitamins, metabolic errors due to genetic abnormalities may relate significantly to ranges of intake needed to avoid deficiency or excess.


Any of the organs may participate in metabolic disease. Two are especially prominent, liver and kidney. The liver enzymes participate in protein, carbohydrate, and fat metabolism. Low protein intake may result in edema due to lack of serum albumin. Liver enzymes help maintain glucose homeostasis, and levels of vitamin and fat metabolism. Common metabolic diseases seen with liver failure include albumin deficiency, hematologic disease, hypoglycemia, abnormalities of vitamin D metabolism, abnormalities of fat metabolism, and metabolism of some of the minerals. The liver also is essential for acid-base homeostasis. The liver enzymes are most responsible for detoxification of various chemicals. Liver failure may manifest itself by high serum ammonia levels and ammonia intoxication. Liver scarring (cirrhosis) may be the end result of several insults. Dietary treatment usually includes a low-protein diet that helps avoid ammonia toxicity and may help hepatic healing. Dietary supply of those substances that cannot be produced because of deficient liver metabolism may mitigate deficiencies partially.

The kidney is important in excreting and conserving water. If the body is alkaline, the kidney secretes base; if the body is acidotic, the kidney secretes acid. The kidney regulates secretion of small proteins, amino acids, and glucose. Kidney disease (nephrosis, where body swelling is related to the loss of serum protein, or nephritis, due to inflammation of the kidney) may result in loss of protein. The kidney is active in the metabolism of vitamin D, and deficiency results in abnormalities of bone and parathyroid metabolism. Kidney disease may result in retention or excess of normal products such as ammonia and urea, or excretion of essential substances such as water. Lack of control of water excretion is renal diabetes insipidus (excessive urine due to kidney abnormality), in contrast to pituitary diabetes insipidus (excessive urine due to pituitary abnormality, resulting in a deficiency of the antidiuretic hormone).

"Inborn errors of metabolism" was a term first used by Sir Archibald Garrod in his Croonian lectures published in 1908. He defined these inborn errors as blocks in metabolic pathways causing genetically determined diseases. He developed the concept that certain diseases of lifelong duration occur because an enzyme governing a single metabolic step is reduced in activity or missing completely, based on his observations of patients with alkaptonuria (urine that turns black upon exposure to light due to the presence of an amino acid breakdown product), albinism (lack of pigment in body tissues, such as hair, due to a lack of enzymes associated with melanin), cystinuria (excessive amounts of the amino acid cystine in urine resembling a form of kidney stone), and pentosuria (abnormal excretion in the urine of pentose, a form of sugar not utilized by humans).

When Garrod diagnosed these patients, most were adults who had been asymptomatic in infancy and childhood. Moreover, he noted that these conditions occurred in families and in many of the families more than one sibling was affected. Parents and other relatives usually were normal. A high incidence of intermarriage was common among affected families.

Following Garrod's work, others began to look for distinguishing characteristics in related families. For example, in 1934, Folling was working in an institution for the mentally delayed. He tested urine with a chemical, ferric chloride, and found a number of severely retarded children and adults whose urine turned purple upon that reagent's addition. The cause of the color change was found to be due to phenyl ketone. He and others determined that the phenyl ketone resulted from an error in the metabolism of phenylalanine, an amino acid found in nearly all proteins ( Jervis). Many patients were identified with phenylketonuria (PKU) over the next twenty years, but little could be done to prevent mental delays that accompanied this condition.

Though chromatography was invented in Russia at the end of the nineteenth century, it was a technique used mainly for identification of complex substances. In the early 1950s, a number of investigators, particularly Armstrong and co-workers (Armstrong et al.), developed a technique to remove phenylalanine from milk proteins and the ability to diagnose this condition in growing infants became available. A formula with low phenylalanine content was developed at about this time. This formula was prescribed for those diagnosed with PKU and is very similar to the formula that is fed infants with phenylketonuria today. Though the infants with phenylketonuria progressed better than previously and indeed some progressed normally, a large number continued to experience delays in mental development. It was not until the Guthrie test was developed in the mid-1960s (Guthrie) that the diagnosis of phenylketonuria could be made almost at birth. This permitted the diet to be started at a much younger age. Many patients treated from birth progress normally.

Phenylketonuria is due to a disorder of the phenylalanine hydroxylating system. The gene for phenylalanine hydroxylase has been localized. Phenylalanine hydroxylase converts phenylalanine to tyrosine. Excess phenylalanine may be toxic or may convert to other toxic substances, or lack of the product tyrosine may be detrimental. Attempts to treat PKU only with added tyrosine did not completely correct the condition.

Newer instrumentation, gene analysis, and dietary control permit screening of the newborn for a large number of amino acid and other abnormalities; thus, many inborn errors of metabolism can be identified in the newborn and for some of these effective or palliative treatment is instituted. The studies of PKU are a model for many of the errors of amino acid metabolism (Barness and Barness). Each of these inborn errors of metabolism may present as a medical emergency, particularly in the newborn. One group of amino acids, termed branch-chain amino acids because of their chemical structure, improperly may form substances that smell like maple syrup. The disease is called maple syrup urine disease. Its treatment requires adjusting the intake of the branched-chain amino acids. Another group of branched-chain amino acids results in severe acidosis and depression of the bone marrow when inadequately metabolized. Two disorders are relatively common, methylmalonic acidemia and propionic acidemia. Some of these individuals respond to diet manipulation and large doses of vitamin B12. Some patients present with an odor of sweaty feet due to a defect in the metabolism of leucine, one branched-chain amino acid. Decreasing dietary protein may ameliorate some of the worst signs of this disease.

One group of infants with amino acid and metabolic error may present with the odor of ammonia. They may become comatose rapidly. They have errors related to the breakdown into urea of one of the five amino acids. They cannot make urea from ammonia. Urea is a benign substance easily excreted in the urine. Affected infants are treated with a low-protein diet and frequently must also be treated with dialysis and ammonia-binding drugs to prevent catastrophic effects to the nervous system (Brusilow et al.).

Fatty acid metabolic disorders are causes of several muscle weakness diseases. Some patients affected by these conditions present with high blood ammonia, heart abnormalities, and coma. Liver disease may be a complication (DeVivo). These are divided according to the size (length) of the implicated fat. Many of the affected fats normally are excreted conjugated to the amino acid carnitine. Some of the worst effects of these disorders respond to the administration of carnitine and to limited intakes of the implicated fatty acid. Symptoms are aggravated by fasting, and intravenous glucose may be required.

Mason and Turner in 1935 reported a reducing substance identified as galactose in the urine of a number of children who were delayed markedly in development. The substance was found to be galactose and its source was human or cow's milk. Very young infants with the abnormal urinary substance were identified by this test. If allowed to drink milk, these infants frequently had seizures, became jaundiced, and vomited perniciously. They did not grow well. When milk was removed from the diet, they seemed to thrive. They experienced improved growth when they were fed with a soybean-based formula that contained no lactose, the principal sugar found in milks, human and other. Lactose is normally digested to galactose and glucose. The condition is called galactosemia because of the abnormally elevated galactose concentration in the blood.

Since the discovery and treatment of galactosemia, other errors in the metabolism of carbohydrates have been recognized. Some children cannot utilize fructose and develop symptoms similar to those experienced by untreated galactosemics. Children with hereditary fructose intolerance are interesting in that they consume breast milk and infant formulas made with lactose without difficulty. However, when given any food with table sugar, their symptoms become frightening. They quickly learn to avoid sugar or any food containing the fruit sugar, fructose. They grow normally and have wonderfully noncarious teeth. Other diseases of carbohydrate metabolism result in liver, heart, and kidney abnormalities. Some are accompanied by physical abnormalities.

Pauling and colleagues (1949) studied hemoglobin structure and found a specific mutation causing an alteration in the structure of hemoglobin. This led to the discovery of the errors in sickle cell disease. Subsequently, other genetic abnormalities have been identified as responsible for many hereditary anemias.

A common disease in adults is arteriosclerotic heart disease. Genetic abnormalities in cholesterol metabolism are believed to be responsible for atherosclerotic heart disease in some who suffer from this condition. Dietary manipulations and exercise beneficially affect a large percentage of these individuals. Others require drugs. Another group of patients with heart disease demonstrates a defect in metabolism of the amino acid homocystine. Treatment of the elevated homocystine with the same agents used for the treatment of the inborn error homo-cystinuria may reverse the condition.

Over four hundred inborn errors of metabolism have been diagnosed. Future genetic studies may reveal many more. Many carbohydrate, amino acid, and fatty acid abnormalities have yielded to effective treatment that must be maintained lifelonga form of treatment is available for approximately forty to fifty of these conditions, with a similar number having experimental approaches. Some complex abnormalities, particularly those related to body structures and muscle diseases, await gene modification for effective therapy. Although each of the inborn errors, excluding the more common hematologic ones, may occur in only 1 in 4,000 to 1 in 100,000 live births, cumulatively they account for more than 1 in 1,000 of live births. Early diagnosis may prevent severe disabilities in progeny.

See also Health and Disease; Microbiology; Proteins and Amino Acids.


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Barness, E. G., and L. Barness. Metabolic Diseases. Foundations of Clinical Management, Genetics, and Pathology. Natick, Mass.: Eaton Publishers, 2000.

Brusilow, S. W., M. L. Batshaw, and L. Waber. "Neonatal Hyperammonemic Coma." Advances in Pediatrics 29 (1982): 6986.

DeVivo, D. C. "Reye Syndrome." Neurologic Clinics 3 (1985): 95114.

Garrod, A. E. "Inborn Errors of Metabolism (Croonian Lectures)." Lancet 2 (1908): 14.

Guthrie, R. "Blood Screening for Phenylketonuria." Journal of the American Medical Association 178 (1961): 863866.

Jervis, G. A. "Studies of Phenylpypyruvic Oligophremia: The Position of the Metabolic Error." Journal of Biological Chemistry 169 (1947): 651654.

Mason, H. H., and M. E. Turner. "Chronic Galactosemia." American Journal of Diseases of Childhood 50 (1935): 359364.

Pauling, I., H. A. Itano, S. J. Singer, and I. C. Wells. "Sickle Cell Anemia: A Molecular Disease." Science 110 (1949): 543545.

Lewis A. Barness