An Introduction to Metabolic Disorder


A metabolic disorder is a medical disorder which affects the production of energy within individual animal cells. Most metabolic disorders are genetic, though a few are "acquired" as a result of diet, toxins, infections, etc. Genetic metabolic disorders are also known as inborn errors of metabolism. Because of the enormous number of these diseases and wide range of systems affected, nearly every "presenting complaint" to a doctor may have a congenital metabolic disease as a possible cause, especially in childhood.

Most of the foods and drinks people ingest are complex materials that the body must break down into simpler substances. This process may involve several steps. The simpler substances are then used as building blocks, which are assembled into the materials the body needs to sustain life. The process of creating these materials may also require several steps. The major building blocks are carbohydrates, amino acids, and fats (lipids). This complicated process of breaking down and converting the substances ingested is called metabolism.

Metabolism is carried out by chemical substances called enzymes, which are made by the body. If a genetic abnormality affects the function of an enzyme or causes it to be deficient or missing altogether, various disorders can occur. The disorders usually result from an inability to break down some substance that should be broken down—so that some intermediate substance that is toxic builds up—or from an inability to produce some essential substance. Metabolic disorders are classified by the particular building block that is affected.

Some hereditary disorders of metabolism (such as phenylketonuria and the lipidoses) can be diagnosed in the fetus using amniocentesis or chorionic villus sampling. Usually, the diagnosis of a hereditary disorder of metabolism is made using a blood test or an examination of a tissue sample to determine whether a specific enzyme is deficient or missing.

In general, the genetic metabolic disorders are caused by genetic defects that result in missing or improperly constructed enzymes necessary for some step in the metabolic process of the cell.

Symptoms of Metabolic Disorder

The following are examples of potential manifestations affecting each of the major organ systems:

* Growth failure, failure to thrive, weight loss
* Ambiguous genitalia, delayed puberty, precocious puberty
* Developmental delay, seizures, dementia, encephalopathy, stroke
* Deafness, blindness, pain agnosia
* Skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth, lumps and bumps
* Dental abnormalities
* Immunodeficiency, thrombocytopenia, anemia, enlarged spleen, enlarged lymph nodes
* Many forms of cancer
* Recurrent vomiting, diarrhea, abdominal pain
* Excessive urination, renal failure, dehydration, edema
* Hypotension, heart failure, enlarged heart, hypertension, myocardial infarction
* Hepatomegaly, jaundice, liver failure
* Unusual facial features, congenital malformations
* Excessive breathing (hyperventilation), respiratory failure
* Abnormal behavior, depression, psychosis
* Joint pain, muscle weakness, cramps
* Hypothyroidism, adrenal insufficiency, hypogonadism, diabetes mellitus

The largest classes of metabolic disorders are:

* Disorders of carbohydrate metabolism
* Disorders of amino acid metabolism
* Disorders of organic acid metabolism (organic acidurias)
* Disorders of fatty acid oxidation and mitochondrial metabolism
* Disorders of porphyrin metabolism
* Disorders of purine or pyrimidine metabolism
* Disorders of steroid metabolism
* Disorders of mitochondrial function
* Disorders of peroxisomal function
* Lysosomal storage disorders

A fourth class, the channelopathies (some of which cause periodic paralysis and/or malignant hyperthermia) could be considered to be metabolic disorders as well, though they are not always classified as such. These disorders affect the ion channels in the cell and organelle membranes, resulting in improper or inefficient transfer of ions through the membranes.

There are also a number of other metabolic disorders (such as myoadenylate deaminase deficiency) which do not cleanly fit into any of the above classifications.

Major categories of inherited metabolic diseases

Traditionally the inherited metabolic diseases were categorized as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases. In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Following are some of the major classes of congenital metabolic diseases, with prominent examples of each class. Many others do not fall into these categories. ICD-10 codes are provided where available.

* Disorders of carbohydrate metabolism
o E.g., glycogen storage disease (E74.0)
* Disorders of amino acid metabolism
o E.g., phenylketonuria (E70.0), maple syrup urine disease (E71.0), glutaric acidemia type 1
* Disorders of organic acid metabolism (organic acidurias)
o E.g., alcaptonuria (E70.2)
* Disorders of fatty acid oxidation and mitochondrial metabolism
o E.g., medium chain acyl dehydrogenase deficiency (glutaric acidemia type 2)
* Disorders of porphyrin metabolism
o E.g., acute intermittent porphyria (E80.2)
* Disorders of purine or pyrimidine metabolism
o E.g., Lesch-Nyhan syndrome (E79.1)
* Disorders of steroid metabolism
o E.g., congenital adrenal hyperplasia (E25.0)
* Disorders of mitochondrial function
o E.g., Kearns-Sayre syndrome (H49.8)
* Disorders of peroxisomal function
o E.g., Zellweger syndrome (Q87.8)
* Lysosomal storage disorders
o E.g., Gaucher's disease (E75.22)

Diagnostic Techniques

Because of the multiplicity of conditions, many different diagnostic tests are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis.

Common screening tests used in the last sixty years:

* Ferric chloride test (turned colors in reaction to various abnormal metabolites in urine)
* Ninhydrin paper chromatography (detected abnormal amino acid patterns)
* Guthrie bacterial inhibition assay (detected a few amino acids in excessive amounts in blood)
* Quantitative plasma amino acids, quantitative urine amino acids
* Urine organic acids by mass spectrometry

Specific diagnostic tests (or focused screening for a small set of disorders):

* Tissue biopsy or necropsy: liver, muscle, brain, bone marrow
* Skin biopsy and fibroblast cultivation for specific enzyme testing
* Specific DNA testing

Amino Acid Metabolism

Amino acids are the building blocks of proteins and have many functions in the body. Hereditary disorders of amino acid processing can be the result of defects either in the breakdown of amino acids or in the body's ability to get the amino acids into cells. Because these disorders produce symptoms early in life, newborns are routinely screened for several common ones. In the United States, newborns are commonly screened for phenylketonuria, maple syrup urine disease, homocystinuria, tyrosinemia, and a number of other inherited disorders, although screening varies from state to state.


Phenylketonuria (PKU) is a disorder that causes a buildup of the amino acid phenylalanine, which is an essential amino acid that cannot be synthesized in the body but is present in food. Excess phenylalanine is normally converted to tyrosine, another amino acid, and eliminated from the body. Without the enzyme that converts it to tyrosine, phenylalanine builds up in the blood and is toxic to the brain, causing mental retardation.

PKU occurs in most ethnic groups. If PKU runs in the family and DNA is available from an affected family member, amniocentesis or chorionic villus sampling with DNA analysis can be performed to determine whether a fetus has the disorder.

Most affected newborns are detected during routine screening tests. Newborns with PKU rarely have symptoms right away, although sometimes an infant is sleepy or eats poorly. If not treated, affected infants progressively develop mental retardation over the first few years of life, which eventually becomes severe. Other symptoms include seizures, nausea and vomiting, an eczema-like rash, lighter skin and hair than their family members, aggressive or self-injurious behavior, hyperactivity, and sometimes psychiatric symptoms. Untreated children often give off a "mousy" body and urine odor as a result of a by-product of phenylalanine (phenylacetic acid) in their urine and sweat.

To prevent mental retardation, phenylalanine intake must be restricted (but not eliminated altogether as people need some phenylalanine to live) beginning in the first few weeks of life. Because all natural sources of protein contain too much phenylalanine for children with PKU, affected children cannot have meat, milk, or other common foods that contain protein. Instead, they must eat a variety of phenylalanine-free processed foods, which are specially manufactured. Low-protein natural foods, such as fruits, vegetables, and restricted amounts of certain grain cereals, can be eaten.

A restricted diet, if started early and maintained well, allows for normal development. However, if very strict control of the diet is not maintained, affected children may begin to have difficulties in school. Dietary restrictions started after 2 to 3 years of age may control extreme hyperactivity and seizures and raise the child's eventual IQ but do not reverse mental retardation. Recent evidence suggests that functioning of some mentally retarded adults with PKU (born before newborn screening tests were available) may improve when they follow the PKU diet.

A phenylalanine-restricted diet should continue for life or intelligence may decrease and neurologic and psychiatric problems may ensue.

Maple Syrup Urine Disease

Children with maple syrup urine disease are unable to metabolize certain amino acids. By-products of these amino acids build up, causing neurologic changes, including seizures and mental retardation. These by-products also cause body fluids, such as urine and sweat, to smell like maple syrup. This disease is most common among Mennonite families.

There are many forms of maple syrup urine disease; symptoms vary in severity. In the most severe form, infants develop neurologic abnormalities, including seizures and coma, during the first week of life and can die within days to weeks. In the milder forms, children initially appear normal but develop vomiting, staggering, confusion, coma, and the odor of maple syrup particularly during physical stress, such as infection or surgery.

In some states, newborns are routinely screened for this disease with a blood test.

Infants with severe disease are treated with dialysis (see Sleep Apnea). Some children with mild disease benefit from injections of the vitamin B1 (thiamin). After the disease has been brought under control, children must always consume a special artificial diet that is low in the particular amino acids that are affected by the missing enzyme.


Children with homocystinuria are unable to metabolize the amino acid homocysteine, which, along with certain toxic by-products, builds up to cause a variety of symptoms. Symptoms may be mild or severe, depending on the particular enzyme defect.

Infants with this disorder are normal at birth. The first symptoms, including dislocation of the lens of the eye, causing severely decreased vision, usually begin after 3 years of age. Most children have skeletal abnormalities, including osteoporosis; the child is usually tall and thin with a curved spine, elongated limbs, and long, spiderlike fingers. Psychiatric and behavioral disorders and mental retardation are common. Homocystinuria makes the blood more likely to spontaneously clot, resulting in strokes, high blood pressure, and many other serious problems.

In a few states, children are screened for homocystinuria at birth with a blood test. The diagnosis is confirmed by a test measuring enzyme function in liver or skin cells.

Some children with homocystinuria improve when given vitamin B6 (pyridoxine) or vitamin B12 (cobalamin).


Children with tyrosinemia are unable to completely metabolize the amino acid tyrosine. By-products of this amino acid build up, causing a variety of symptoms. In some states, the disorder is detected on the newborn screening tests.

There are two main types of tyrosinemia: I and II. Type I tyrosinemia is most common in children of French-Canadian or Scandinavian descent. Children with this disorder typically become ill sometime within the first year of life with dysfunction of the liver, kidneys, and nerves, resulting in irritability, rickets, or even liver failure and death. Restriction of tyrosine in the diet is of little help. An experimental drug, which blocks production of toxic metabolites, may help children with type I tyrosinemia. Often, children with type I tyrosinemia require a liver transplant.

Type II tyrosinemia is less common. Affected children sometimes have mental retardation and frequently develop sores on the skin and eyes. Unlike type I tyrosinemia, restriction of tyrosine in the diet can prevent problems from developing.

Carbohydrate Metabolism

Carbohydrates are sugars. Some sugars are simple, and others are more complex. Sucrose (table sugar) is made of two simpler sugars called glucose and fructose. Lactose (milk sugar) is made of glucose and galactose. Both sucrose and lactose must be broken down into their component sugars by enzymes before the body can absorb and make use of them. The carbohydrates in bread, pasta, rice, and other carbohydrate-containing foods are long chains of simple sugar molecules. These longer molecules must also be broken down by the body. If an enzyme needed to process a certain sugar is missing, the sugar can accumulate in the body, causing problems.

Glycogen Storage Diseases

Glycogen is made of many glucose molecules linked together. The sugar glucose is the body's main source of energy for the muscles (including the heart) and brain. Any glucose that is not immediately used for energy is held in reserve in the liver, muscles, and kidneys in the form of glycogen and released when needed by the body.

There are many different glycogen storage diseases (also called glycogenoses), each identified by a roman numeral. These diseases are caused by a hereditary lack of one of the enzymes that is essential to the process of forming glucose into glycogen and breaking down glycogen into glucose. About 1 in 20,000 infants has some form of glycogen storage disease.

Some of these diseases cause few symptoms; others are fatal. The specific symptoms, age at which symptoms start, and their severity vary considerably among these diseases. For types II, V, and VII, the main symptom is usually weakness. For types I, III, and VI, symptoms are low levels of sugar in the blood and protrusion of the abdomen (because excess or abnormal glycogen may enlarge the liver). Low levels of sugar in the blood cause weakness, sweating, confusion, and sometimes seizures and coma. Other consequences for children may include stunted growth, frequent infections, or sores in the mouth and intestines. Glycogen storage diseases tend to cause uric acid, a waste product, to accumulate in the joints (which can cause gout) and in the kidneys (which can cause kidney stones). In type I glycogen storage disease, kidney failure is common in the second decade of life or later.

The specific diagnosis is made when a chemical examination of a sample of tissue, usually muscle or liver, determines that a specific enzyme is missing.

Treatment depends on the type of glycogen storage disease. For many people, eating many small carbohydrate-rich meals every day helps prevent blood sugar levels from dropping. For people who have glycogen storage diseases that produce low blood sugar, glucose levels are maintained by giving uncooked cornstarch every 4 to 6 hours around the clock. Sometimes carbohydrate solutions are given through a stomach tube all night to prevent low blood sugar levels from occurring at night.


Galactosemia (a high blood level of galactose) is caused by lack of one of the enzymes necessary for metabolizing galactose, a sugar present in lactose (milk sugar). A metabolite builds up that is toxic to the liver and kidneys and also damages the lens of the eye, causing cataracts.

A newborn with galactosemia seems normal at first but within a few days or weeks loses his appetite, vomits, becomes jaundiced, has diarrhea, and stops growing normally. White blood cell function is affected, and serious infections can develop. If treatment is delayed, affected children remain short and become mentally retarded or may die.

Galactosemia is detectable with a blood test. This test is performed as a routine screening test on newborns in nearly all states in the United States and particularly in those with a family member known to have the disorder.

Galactosemia is treated by completely eliminating milk and milk products—the source of galactose—from an affected child's diet. Galactose is also present in some fruits, vegetables, and sea products, such as seaweed. Doctors are not sure whether the small amounts in these foods cause problems in the long term. People who have the disorder must restrict galactose intake throughout life.

If galactosemia is recognized at birth and adequately treated, the liver and kidney problems do not develop, and initial mental development is normal. However, even with proper treatment, children with galactosemia often have a lower intelligence quotient (IQ) than their siblings, and they often have speech problems. Girls often have ovaries that do not function, and only a few are able to conceive naturally. Boys, however, have normal testicular function.

Hereditary Fructose Intolerance

In this disorder, the body is missing an enzyme that allows it to use fructose, a sugar present in table sugar (sucrose) and many fruits. As a result, a by-product of fructose accumulates in the body, blocking the formation of glycogen and its conversion to glucose for use as energy. Ingesting more than tiny amounts of fructose or sucrose causes low blood sugar levels (hypoglycemia), with sweating, confusion, and sometimes seizures and coma. Children who continue to eat foods containing fructose develop kidney and liver damage, resulting in jaundice, vomiting, mental deterioration, seizures, and death. Chronic symptoms include poor eating, failure to thrive, digestive symptoms, liver failure, and kidney damage.

The diagnosis is made when a chemical examination of a sample of liver tissue determines that the enzyme is missing. Treatment involves excluding fructose (generally found in sweet fruits), sucrose, and sorbitol (a sugar substitute) from the diet. Acute attacks respond to glucose given intravenously; milder attacks of hypoglycemia are treated with glucose tablets, which should be carried by anyone who has hereditary fructose intolerance.

Lipid Metabolism

Fats (lipids) are an important source of energy for the body. The body's store of fat is constantly broken down and reassembled to balance the body's energy needs with the food available. Groups of specific enzymes help the body break down and process fats. Certain abnormalities in these enzymes can lead to the buildup of specific fatty substances that normally would have been broken down by the enzymes. Over time, accumulations of these substances can be harmful to many organs of the body. Disorders caused by the accumulation of lipids are called lipidoses. Other enzyme abnormalities result in the body being unable to properly convert fats into energy. These abnormalities are called fatty acid oxidation disorders.

Gaucher's Disease

In Gaucher's disease, glucocerebrosides, which are a product of fat metabolism, accumulate in tissues. Gaucher's disease is the most common lipidosis. The disease is most common in Ashkenazi (Eastern European) Jews. Gaucher's disease leads to an enlarged liver and spleen and a brownish pigmentation of the skin. Accumulations of glucocerebrosides in the eyes cause yellow spots called pingueculae to appear. Accumulations in the bone marrow can cause pain and destroy bone.

Most people who have Gaucher's disease develop type 1, the chronic form, which results in an enlarged liver and spleen and bone abnormalities. Most are adults, but children also may have type 1. Type 2, the infantile form, develops in infancy; infants with the disease have an enlarged spleen and severe nervous system abnormalities and usually die within a year. Type 3, the juvenile form, can begin at any time during childhood. Children with the disease have an enlarged liver and spleen, bone abnormalities, and slowly progressive nervous system abnormalities. Children who survive to adolescence may live for many years.

Many people with Gaucher's disease can be treated with enzyme replacement therapy, in which enzymes are given intravenously, usually every 2 weeks. Enzyme replacement therapy is most effective for people who do not have nervous system complications.

Tay-Sachs Disease

In Tay-Sachs disease, gangliosides, which are products of fat metabolism, accumulate in tissues. The disease is most common in families of Eastern European Jewish origin. At a very early age, children with this disease become progressively retarded and appear to have floppy muscle tone. Spasticity develops and is followed by paralysis, dementia, and blindness. These children usually die by age 3 or 4. Tay-Sachs disease can be identified in the fetus by chorionic villus sampling or amniocentesis. The disease cannot be treated or cured.

Niemann-Pick Disease

In Niemann-Pick disease, the deficiency of a specific enzyme results in the accumulation of sphingomyelin (a product of fat metabolism) or cholesterol. Niemann-Pick disease has several forms, depending on the severity of the enzyme deficiency and thus accumulation of sphingomyelin or cholesterol. The most severe forms tend to occur in Jewish people. The milder forms occur in all ethnic groups.

In the most severe form (type A), children fail to grow properly and have multiple neurologic problems. These children usually die by age 3. Children with type B disease develop fatty growths in the skin, areas of dark pigmentation, and an enlarged liver, spleen, and lymph nodes; they may be mentally retarded. Children with type C disease develop symptoms in childhood, with seizures and neurologic deterioration.

Some forms of Niemann-Pick disease can be diagnosed in the fetus by chorionic villus sampling or amniocentesis. After birth, the diagnosis can be made by a liver biopsy (removal of a tissue specimen for examination under a microscope). None of the types of Niemann-Pick disease can be cured, and children tend to die of infection or progressive dysfunction of the central nervous system.

Fabry's Disease

In Fabry's disease, glycolipid, which is a product of fat metabolism, accumulates in tissues. Because the defective gene for this rare disorder is carried on the X chromosome, the full-blown disease occurs only in males (see Genetics: Replication). The accumulation of glycolipid causes noncancerous skin growths (angiokeratomas) to form over the lower part of the trunk. The corneas become cloudy, resulting in poor vision. A burning pain may develop in the arms and legs, and the person may have episodes of fever. People with Fabry's disease eventually develop kidney failure and heart disease, although most often they live into adulthood. Kidney failure may lead to high blood pressure, which may result in stroke.

Fabry's disease can be diagnosed in the fetus by chorionic villus sampling or amniocentesis. The disease cannot be cured or even treated directly, but researchers are investigating a treatment in which the deficient enzyme is replaced by transfusion. Treatment consists of taking analgesics to help relieve pain and fever. People with kidney failure may need a kidney transplant.

Fatty Acid Oxidation Disorders

Several enzymes help break fats down so that they may be turned into energy. An inherited defect or deficiency of one of these enzymes leaves the body short of energy and allows breakdown products, such as acyl-CoA, to accumulate. The enzyme most commonly deficient is medium chain acyl-CoA dehydrogenase (MCAD). MCAD deficiency is one of the most common inherited disorders of metabolism, particularly in people of Northern European descent.

Symptoms usually develop between birth and age 3. Children are most likely to develop symptoms if they go without food for a period of time (which depletes other sources of energy) or have an increased need for calories because of exercise or illness. The level of sugar in the blood drops significantly, causing confusion or coma. The child becomes weak and may have vomiting or seizures. Over the long term, children have delayed mental and physical development, an enlarged liver, heart muscle weakness, and an irregular heartbeat. Sudden death may occur.

Some states screen newborns for MCAD deficiency with a blood test. Immediate treatment is with intravenous glucose. For long-term treatment, the child must eat often, never skipping meals, and consume a diet high in carbohydrates and low in fats. Supplements of the amino acid carnitine may be helpful. The long-term outcome is generally good.

Peruvate Metabolism

Pyruvate is a substance formed in the processing of carbohydrates and proteins that serves as an energy source for cells. Problems with pyruvate metabolism can limit a cell's ability to produce energy and allow a buildup of lactic acid, a waste product. Many enzymes are involved in pyruvate metabolism. A hereditary deficiency in any one of these enzymes results in one of a variety of disorders, depending on which enzyme is missing. Symptoms may develop any time between early infancy and late adulthood. Exercise and infections can worsen symptoms, leading to severe lactic acidosis. These disorders are diagnosed by measuring enzyme activity in cells from the liver or skin.

Pyruvate dehydrogenase complex deficiency is a lack of a group of enzymes needed to process pyruvate. This deficiency results in a variety of symptoms, ranging from mild to severe. Some newborns with this deficiency have brain malformations. Other children appear normal at birth but develop symptoms, including weak muscles, seizures, poor coordination, and a severe balance problem, later in infancy or childhood. Mental retardation is common. This disorder cannot be cured, but some children are helped by a diet that is high in fat and low in carbohydrates.

Absence of pyruvate carboxylase, an enzyme, is a very rare condition that interferes with or blocks the production of glucose from pyruvate in the body. Lactic acid and ketones build up in the blood. Often this disease is fatal. Children who survive have seizures and severe mental retardation, although there are recent reports of children with milder symptoms. There is no cure, but some children are helped by eating frequent carbohydrate-rich meals and restricting dietary protein.

Sci-Tech Encyclopedia: Metabolic disorders

Disorders of metabolism principally involve an imbalance in nucleic acids, proteins, lipids, or carbohydrates. They are usually associated with either a deficiency or excess resulting in an imbalance in a particular metabolic pathway. All metabolic disorders have a genetic background, and some of them are expressed as specific genetic diseases. Other factors affecting metabolism include internal control mechanisms that are superimposed on the genetic background. One of the most important mechanisms is the hormonal control system, which consists of the endocrine, paracrine, and autocrine systems. The second control system that has a significant effect on metabolism is the neural control system. The third control system is the immune control system, which relates to both the endocrine and neural systems. Genetic background, environmental factors, and the three major control mechanisms, in conjunction with age and sex, bring about profound changes in metabolism, which ultimately result in structural and functional alterations. See also Immunology; Nervous system (vertebrate).

Nucleic acids

Abnormalities of nucleic acid metabolism are associated with several diseases, including gout and lupus erythematosus. All genetic disease implies a defect in nucleic acids, and although some genetic diseases are classified as protein abnormalities there is always an inherent defect in the nucleotide. This is either a deficiency, an excess, or a mutation that results in an abnormal protein being formed. Similarly, although lipid storage disease results in an abnormal metabolism of lipids, it is the result of a deficiency of a particular enzyme, which also means a defect in the particular nucleic acid code. In some carbohydrate genetic storage diseases, there is a deficiency of a particular enzyme, which again results from a nucleotide defect. Certain congenital defects that result in malformations of organ systems are the result of either germ cell or somatic cell deficiencies involving differentiation genes composed of nucleic acid.

The genetic disease severe combined immunodeficiency syndrome (SCIDS) results in a deficiency of B lymphocytes, which produce antibody, and T lymphocytes, which are responsible for graft and tumor rejection as a result of their cytotoxic effect. This abnormality is associated with a deficiency of the enzyme adenosine deaminase. See also Arthritis; Connective tissue; Disease; Gout; Human genetics; Nucleic acid.


The diseases associated with protein abnormalities include those associated with increased production of proteins, decreased production of proteins, production of abnormal proteins, and excretion of unusual amounts of amino acids.

Often called macroglobulinemia, hyperproteinemia results in an increase in beta or gamma globulins, but possibly with less total protein. Hyperglobulinemia diseases include multiple myeloma, kala-azar, Hodgkin's disease, lymphogranuloma inguinale, sarcoidosis, cirrhosis, and amyloid disease. They usually involve stem cell lines of the bone marrow macrophages or B cells. See also Cirrhosis; Hodgkin's disease.

A decrease in the amount of protein (hypoproteinemia) can result from a lack of amino acids for protein synthesis, a metabolic block, or other interference with normal protein synthesis. Increased excretion of protein, particularly in chronic renal disease with a loss of albumin in the urine (albuminuria), is another common cause of hypoproteinemia. Kwashiorkor is the best example of hypoproteinemia resulting from dietary deficiency. In hypogammaglobulinemia and agammaglobulinemia, which may also be classified under hypoproteinemia, the total serum albumin and globulin are not markedly depressed, but the gamma globulins may fall from a normal of 15–20% of total protein to 0.4%.

Many diseases are characterized by abnormal proteins, including multiple myeloma, the hemoglobinopathies, and the various amyloid disturbances. Multiple myeloma, a neoplastic growth of plasma cells, particularly in the bone marrow and lymph nodes, is representative of a disease in which an abnormal protein is produced. Another large group of abnormal proteins includes the hemoglobinopathies. Hemoglobin functions in the transport of oxygen in the blood. Scores of different hemoglobins have been identified, but sickle cell in the United States and thalassemia (Mediterranean anemia) in Europe are two of the most common hemoglobin abnormalities. A third type of abnormal protein is found in amyloid disease, of which there are many variations. See also Amyloidosis; Hemoglobin; Sickle cell disease.

A fourth group with abnormal protein metabolism is associated with a change in particular amino acids resulting either from an overflow mechanism, where the concentration of amino acids in the serum surpasses the renal threshold of the glomerular membrane, or from defective absorption of amino acids in renal tubules. Tyrosine appears to be one of the most critical amino acids, and its metabolism is related to four key diseases including phenylketonuria, hypothyroidism, albinism, and alkaptonuria. The liver plays a major role in the deamination of amino acids. Advanced hepatitis and cirrhosis may lead to increased levels of amino acids in the blood and excretion in the urine. Other diseases with amino aciduria that are believed to be the result of defective kidney function include cystinuria (the failure to reabsorb cystine, lysine, arginine, and ornithine), Wilson's disease (a degeneration involving copper metabolism in the liver and brain), Fanconi's syndrome, galactosemia, scurvy, rickets, and lead, cresol, or benzene poisoning. See also Kidney disorders; Liver disorders; Phenylketonuria; Protein metabolism; Sickle cell disease.


Although lipid stores remain a secondary energy reserve in starvation, the breakdown of lipids associated with diabetes and starvation results in the production of ketone bodies in the urine with general acidosis (ketosis) in the serum. Of concern to many people is an increase in lipids associated with obesity. See also Obesity.

Hyperlipemia, an excess of lipid in the blood, is often secondary to uncontrollable diabetes, hypothyroidism, biliary cirrhosis, and lipoid nephrosis. Excess proliferation of fat cells is known as a lipoma, which occasionally becomes malignant, producing a liposarcoma. See also Arteriosclerosis.

In a large group of genetic lipid storage diseases, lipid accumulates because of a disturbance in lipid metabolism that is independent of external stimuli. These genetic diseases are inherent nucleic acid defects that result in abnormal enzymatic proteins, which then result in abnormal lipid metabolism. In these diseases, a large accumulation of lipid appears in many cells, but particularly the reticuloendothelial cells of the lymph nodes, liver, spleen, and bone marrow. Abnormal lipid storage occurs in Niemann-Pick, Gaucher's, and Tay-Sachs diseases.

The heterozygous form of the genetic disease familial hypercholesteremia results in cholesterol levels two to four times normal, and is characterized by arteriosclerotic lesions of the coronary vessels that cause myocardial infarct and death in the 35–50-year age range. In the homozygous condition, with cholesterol levels eight to ten times normal, death occurs usually before the age of 15. The defect resides in the receptor for low-density lipoprotein (LDL). See also Cholesterol; Heart disorders; Lipid metabolism.


Abnormal carbohydrate diseases include the genetic diseases that represent a deficiency in nucleotide and eventually protein enzymatic activity. Of the six common carbohydrate storage diseases, two examples are von Gierke's disease, marked by glycogen storage in the heart, and Pompes' disease, in which the carbohydrate is stored in the liver. Variants of carbohydrate disease involve storage of mucopolysaccharides, as in Hurler's disease, and storage of galactose, as in galactosemia.

The most important disease associated with carbohydrate metabolism is diabetes mellitus.

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