Metabolic Disorders

Endocrine metabolic disorders (EMDs) are caused by the overproduction or underproduction of a specific hormone. While most EMDs are the result of an imbalance without a genetic root, congenital adrenal hyperplasia (CAH) is genetically based. CAH is a malfunction of steroid hormone synthesis in the adrenals caused by a defective enzyme, 21 hydroxylase. The enzyme triggers an overproduction of testosterone that can masculinize females. CAH can be stabilized by cortisol treatment, allowing patients to have normal life spans. Some of the most studied EMDs include Cushing's syndrome, diabetes mellitus, hypothydroidism, and hyperthyrodism.

Cushing's syndrome is caused by the hypersecretion of cortisol by cells in the adrenal cortex. Hypersecretion can be due to overstimulation of cortisol-releasing mechanisms by excess ACTH, a pituitary hormone. Cushing's can result from pituitary or adrenal tumors. It is further characterized by obesity, a rounded face, muscle weakness, a tendency to bruise easily, and numerous other complications.

Diabetes mellitus (DM) is a metabolic carbohydrate disorder that results from either insufficient insulin (type 1 DM) or the body's inability to recognize available insulin (type 2 DM). DM is a multifactorially inherited disorder; this means that although people can inherit a propensity toward this condition, environment and diet can trigger onset of the actual disease. People who suffer from DM experience abnormally high blood glucose levels, excessive thirst and urine output, weight loss, and fatigue. DM can lead to lipid metabolism disorders as well. Ironically, one of the triggering symptoms of DM is obesity. Type 1 DM, called insulin-dependent diabetes, because it requires routine insulin injections, usually appears before age 35. Type 2 DM, called non-insulin dependent diabetes because it can be regulated by diet, weight control, and oral medication, usually does not appear until after age 40 years. Some women develop gestational diabetes, a temporary form of DM that appears during pregnancy and requires special prenatal care. Physicians routinely check the glucose levels of pregnant women at around 26 gestational weeks. Gestational diabetes usually disappears after delivery.

Hypothyrodism and hyperthyroidism can both be due to a number of causes, one of which is metabolic dysfunction. Hypothyroidism is caused by undersecretion, of thyroid hormones. In one form of childhood hypothyroidism, children born with abnormally small thyroids produce insufficient levels of the thyroid hormones T3 and T4, which are important for metabolically directed bone development. If detected in the first 6 months of life, this disorder can be treated with synthetic thyroid hormones such that its effects can be avoided. The most severe early onset hypothyroidisms are characterized by Cretinism, a type of dwarfism, and mental retardation. Adult hypothyroidism is called myxedema. Myxedema symptoms include slowed speech, yellowed skin, and generally slowed body functions. Myxedema can also be treated with synthetic T4, but if left untreated, can lead to coma.

Hyperthyroidism, caused by oversecretion of thyroid hormones, is marked by an overall rapid metabolism including a rapid pulse, high body temperature, and agitation. The most common form of hyperthyroidism in children and adults is Grave's disease, which is clinically distinguished by the appearance of an enlarged thyroid, or goiter, that grows at the front of the neck. Grave's disease is thought to be a malfunction of the immunological functions involving the thyroid.

There are several other metabolic disorders, but because they are not very common, not much is known about them. For example, a disease known as amyloidosis results when enough amyloid protein builds up in one or more organs to cause the organ(s) to malfunction. The heart, kidneys, nervous system and gastrointestinal tract are most often affected. Amyloid (pronounced am'i-loyd) is an abnormal protein that may be deposited in any of the body's tissues or organs. This abnormal protein comes from cells in the bone marrow, so amyloidosis is known as a bone marrow disease. The bone marrow makes protective antibodies that protect against infection and disease. After they have served their function, these antibodies are broken down and recycled by the body. In amyloidosis, cells in the bone marrow produce antibodies that cannot be broken down. These antibodies then begin to build up in the bloodstream. Ultimately, they leave the bloodstream and are deposited in the tissues as amyloid.

Symptoms of amyloidosis depend on the organs it affects. The wide range of symptoms often makes amyloidosis difficult to diagnose. Symptoms can include:

• swelling of ankles and legs
• weakness and severe fatigue
• weight loss
• shortness of breath
• numbness or tingling in the hands or feet
• enlarged tongue
• feeling of fullness after eating smaller amounts of food than usual
• dizziness upon standing

A physical examination is necessary to find out if the organs are functioning properly. Blood, urine and bone marrow tests may also be done. A small tissue sample (biopsy) may be taken from the rectum, abdominal fat or bone marrow to determine if the person has amyloidosis. These biopsies are relatively minor procedures done in an outpatient setting with a local anesthetic. Occasionally, samples are taken from the liver, nerve, heart or kidney. This may require hospitalization and can help diagnose the specific organ affected by amyloidosis. Blood or urine tests can detect the protein, but only bone marrow tests or other small samples of tissue can positively establish the diagnosis of amyloidosis.

The goal of treatment for amyloidosis is to limit further production of the amyloid protein. This is done with medications and diet. Well-balanced nutrition is important to provide the body with an adequate energy supply.

Another metabolic disorder that is hereditary and little known is hypophosphatasia. Hypophosphatasia is an inherited metabolic (chemical) bone disease that results from low levels of an enzyme called alkaline phosphatase (ALP). ALP is normally present in large amounts in bones and the liver. In hypophosphatasia, abnormalities in the gene that makes ALP lead to the production of inactive ALP. Subsequently, several chemicals, including phosphoethanolamine, pyridoxal 5/-phosphate (a form of vitamin B₆) and inorganic pyrophosphate, accumulate in the body and are found in large amounts in the blood and urine. It appears that the accumulation of inorganic pyrophosphate is the cause of the characteristic defective calcification of bones seen in infants and children (rickets) and in adults (osteomalacia).

The severity of hypophosphatasia is remarkably variable from patient to patient. The most severely affected fail to form a normal skeletal in the womb and are stillborn. The mildly affected patients may show only low levels of ALP in the blood, yet never suffer bone problems. In general, patients are categorized as having perinatal, infantile, childhood, or adult hypophosphatasia depending on the severity of the disease and the age at which the bony manifestations are first detected. The x ray changes are quite distinct to the trained eye, and the diagnosis is substantiated by measuring ALP in a routine blood test. It is important that the doctors use appropriate age ranges for normal ALP levels when interpreting the blood test.

The outcome following a diagnosis of hypophosphatasia is variable. Cases detected in the womb or with severe deformities at birth almost always result in death within days or weeks. When the diagnosis is made before six months of age, some infants have a downhill course while others survive and even do well. When diagnosed during childhood, underlying rickets may or may not result in the presence of skeletal deformities. Premature loss of teeth when the child is under the age of five is the most usual manifestation. Adults may be troubled by recurring fractures in their feet and painful, partial fractures in their thigh bones. There is no established medical therapy for hypophosphatasia.

The severe perinatal and infantile forms of hypophosphatasia are inherited as autosomal recessive conditions. The patient receives one defective gene from each parent. Some of the more mild childhood and adult cases are also inherited this way. More mild adult cases are inherited in an autosomal dominant pattern where the patient gets just one defective gene from one parent. Individuals with hypophosphatasia and parents of children with this disorder are encouraged to seek genetic counseling to understand the likelihood and severity of hypophosphatasia recurring in their family.

Obesity is probably the oldest metabolic disturbance. People in a society become obese as soon as enough food and leisure are available to cause an imbalance between energy intake and energy expenditure. Obesity is becoming a more important risk factor for the development of diabetes, hypertension and cardiovascular disease. It has multiple causes; the development of obesity is a complex interaction between genetic, psychological, socioeconomic and cultural factors. Individuals have unique genetic and environmental factors that affect how food is processed; there are, therefore, individual differences in susceptibility to obesity.

The major health risks of obesity increase in a curvilinear relationship, with prevalences increasing progressively and disproportionately with increasing weight. Weight increases beginning during adulthood and continuing for many years have the greatest adverse affects. Overweight men have a significantly higher mortality rate for colorectal and prostate cancer; men whose weight is 130% or more above average are 2.5 times more likely to die of prostate cancer during a 20 year follow-up compared to men of average weight. Menopausal women with upper body fat localization have an increased risk of developing breast cancer. Overweight women also have higher rates of cancer of the uterus and ovaries. Obesity is also correlated with increased estrogenicity of cervical smears. These problems may reflect an increase in the conversion of estrone to androstenedion by the stromal elements of adipose tissue.

Obese women, especially those with upper body obesity, show more irregularity in menstrual cycles as well as greater frequency of other menstrual abnormalities than normal weight women. They also have more problems during pregnancy with an increased frequency of toxemia and hypertension. In obese girls, the onset of menarche occurs at a younger age than in normal weight girls. Menstruation is probably initiated when body weight reaches a critical mass.

Currently, a lot of research effort, man power, and money is being spent trying to find a cure for obesity. Several multidisciplinary forums are being set up for research and treatment of massive obesity including surgery, dietetics, nutrition, psychiatry, endocrinology, and weight management counseling.