Erythrocyte Disorders

Anemia

Anemia is a decrease in number of red blood cells (RBCs) or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin deficiency.

Kinds of Anemia

Aplastic Anemia

Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia. Typically, anemia refers to low red blood cell counts, but aplastic anemia patients have lower counts of all three blood cell types: red blood cells, white blood cells, and platelets, termed pancytopenia.

Causes

Aplastic anemia develops when damage occurs to your bone marrow, slowing or shutting down the production of new blood cells. Bone marrow is a red, spongy material inside your bones that produces stem cells, which give rise to other cells. Stem cells in the bone marrow produce blood cells — red cells, white cells and platelets. In aplastic anemia, the bone marrow is described in medical terms as aplastic or hypoplastic — meaning that it's empty (aplastic) or contains very few blood cells (hypoplastic).

Symptoms

Aplastic anemia symptoms result from a shortage of one or more types of blood cells. Signs and symptoms may include:

Fatigue Shortness of breath with exertion

Rapid or irregular heart rate

Pale skin

Frequent or prolonged infections

Unexplained or easy bruising

Nosebleeds and bleeding gums

Prolonged bleeding from cuts

Skin rash

Dizziness

Headache

Aplastic anemia can progress slowly over weeks or months, or it may come on suddenly. The illness may be brief, or it may become chronic. Aplastic anemia can be very severe and even fatal.

Exams and Tests

Blood tests. Normally, red blood cell, white blood cell and platelet levels stay within a certain range. Your doctor may suspect aplastic anemia when all three of these blood cell levels are very low.

Bone marrow biopsy. To confirm a diagnosis, you'll need to undergo a bone marrow biopsy. In this procedure, a doctor uses a needle to remove a small sample of bone marrow from a large bone in your body, such as your hipbone. The bone marrow sample is examined under a microscope to rule out other blood-related diseases. In aplastic anemia, bone marrow contains fewer blood cells than normal.

Once you've received a diagnosis of aplastic anemia, you may need additional tests to determine an underlying cause.

Treatment

Treatments for aplastic anemia may include observation for mild cases, blood transfusions and medications for more serious cases, and, in severe cases, bone marrow transplantation. Severe aplastic anemia, in which your blood cell counts are extremely low, is life-threatening and requires immediate hospitalization for treatment.

Blood transfusionsTreatment for aplastic anemia usually involves blood transfusions to control bleeding and relieve anemia symptoms. Blood transfusions aren't a cure for aplastic anemia. But they do relieve signs and symptoms by providing blood cells that your bone marrow isn't producing. A transfusion may include:

Red blood cells. Transfusions of red blood cells raise red blood cell counts. This helps relieve anemia and fatigue.

Platelets. Transfusions of platelets help prevent excessive bleeding.

While there's generally no limit to the number of blood cell transfusions you can have, complications can sometimes arise with multiple transfusions. Transfused red blood cells contain iron that can accumulate in your body and can damage vital organs if an iron overload isn't treated. Medications can help your body get rid of excess iron. Another possible complication is that over time, your body may develop antibodies to transfused blood cells, making them less effective at relieving symptoms.

Stem cell transplant A stem cell transplant to rebuild the bone marrow with stem cells from a donor may offer the only successful treatment option for people with severe aplastic anemia. A stem cell transplant, which is also called a bone marrow transplant, is generally the treatment of choice for people who are younger and have a matching donor — most often a sibling.

If a donor is found, your diseased bone marrow is first depleted with radiation or chemotherapy. Healthy stem cells from the donor are filtered from the blood. The healthy stem cells are injected intravenously into your bloodstream, where they migrate to the bone marrow cavities and begin

generating new blood cells. The procedure requires a lengthy hospital stay. After the transplant, you'll receive drugs to help prevent rejection of the donated stem cells.

A stem cell transplant carries risks. There's a chance that your body may reject the transplant, leading to life-threatening complications. In addition, not everyone is a candidate for transplantation or can find a suitable donor.

ImmunosuppressantsFor people who can't undergo a bone marrow transplant or for those whose aplastic anemia may be due to an autoimmune disorder, treatment may involve drugs that alter or suppress the immune system (immunosuppressants).

Drugs such as cyclosporine (Gengraf, Neoral, Sandimmune) and anti-thymocyte globulin (Thymoglobulin) are examples. These drugs suppress the activity of immune cells that are damaging your bone marrow. This helps your bone marrow recover and generate new blood cells. Cyclosporine and anti-thymocyte globulin are often used in combination.

Corticosteroids, such as methylprednisolone (Medrol, Solu-Medrol), are often given at the same time as these drugs.

Immune-suppressing drugs can be very effective at treating aplastic anemia. The downside is that these drugs further weaken your immune system. It's also possible that after you stop taking these drugs, aplastic anemia may return.

Bone marrow stimulants Certain drugs — including colony-stimulating factors, such as sargramostim (Leukine), filgrastim (Neupogen) and pegfilgrastim (Neulasta), and epoetin alfa (Epogen, Procrit) — may help stimulate the bone marrow to produce new blood cells. Growth factors are often used in combination with immune-suppressing drugs.

Antibiotics, antivirals Having aplastic anemia weakens your immune system. You have fewer white blood cells in circulation to fight off germs. This leaves you susceptible to infections.

At the first sign of infection, such as a fever, see your doctor. You don't want the infection to get worse, because it could prove life-threatening. If you have severe aplastic anemia, your doctor may give you antibiotics or antiviral medications to help prevent infections.

Iron Deficiency Anemia

is a common anemia that occurs when iron loss (often from intestinal bleeding or menses) occurs, and/or the dietary intake or absorption of iron is insufficient. In iron deficiency, hemoglobin, which contains iron, cannot be formed.

Pathophysiology

Iron is vital for all living organisms because it is essential for multiple metabolic processes, including oxygen transport, DNA synthesis, and electron transport. Iron equilibrium in the body is regulated carefully to ensure that sufficient iron is absorbed in order to compensate for body losses of iron.

Whereas body loss of iron quantitatively is as important as absorption in terms of maintaining iron equilibrium, it is a more passive process than absorption.

In healthy people, the body concentration of iron (approximately 60 parts per million [ppm]) is regulated carefully by absorptive cells in the proximal small intestine, which alter iron absorption to match body losses of iron (see the image below). Persistent errors in iron balance lead to either iron deficiency anemia or hemosiderosis. Both are disorders with potential adverse consequences.

Either diminished absorbable dietary iron or excessive loss of body iron can cause iron deficiency. Diminished absorption usually is due to an insufficient intake of dietary iron in an absorbable form. Hemorrhage is the most common cause of excessive loss of body iron, but it can occur with hemoglobinuria from intravascular hemolysis. Malabsorption of iron is relatively uncommon in the absence of small bowel disease (sprue, celiac disease, regional enteritis) or previous GI surgery.

Iron uptake in the proximal small bowel occurs by 3 separate pathways. These are the heme pathway and 2 distinct pathways for ferric and ferrous iron.

In North America and Europe, one third of dietary iron is heme iron, but two thirds of body iron is derived from dietary myoglobin and hemoglobin. Heme iron is not chelated and precipitated by numerous dietary constituent that render nonheme iron nonabsorbable (see the image below), such as phytates, phosphates, tannates, oxalates, and carbonates. Heme is maintained soluble and available for absorption by globin degradation products produced by pancreatic enzymes. Heme iron and nonheme iron are absorbed into the enterocyte noncompetitively.

Heme enters the cell as an intact metalloporphyrin, presumably by a vesicular mechanism. It is degraded within the enterocyte by heme oxygenase with release of iron so that it traverses the basolateral cell membrane in competition with nonheme iron to bind transferrin in the plasma.

Ferric iron utilizes a different pathway to enter cells than ferrous iron. This was shown by competitive inhibition studies, the use of blocking antibodies against divalent metal transporter-1 (DMT-1) and beta3-integrin, and transfection experiments using DMT-1 DNA. This research indicated that ferric iron utilizes beta3-integrin and mobilferrin, while ferrous iron uses DMT-1 to enter cells.

Which pathway transports most nonheme iron in humans is not known. Most nonheme dietary iron is ferric iron. Iron absorption in mice and rats may involve more ferrous iron because they excrete moderate quantities of ascorbate in intestinal secretions. Humans, however, are a scorbutic species and are unable to synthesize ascorbate to reduce ferric iron.

Other proteins appear to be related to iron absorption. These are stimulators of iron transport (SFT), which are reported to increase the absorption of both ferric and ferrous iron, and hephaestin, which is postulated to be important in the transfer of iron from enterocytes into the plasma. The relationships and interactions among the newly described proteins are not known at this time and are being explored in a number of laboratories.

The iron concentration within enterocytes varies directly with the body’s requirement for iron. Absorptive cells of iron-deficient humans and animals contain little stainable iron, whereas those of subjects who are replete in iron contain significantly higher amounts. Untreated phenotypic hemochromatosis creates little stainable iron in the enterocyte, similar to iron deficiency. Iron within the enterocyte may operate by up-regulation of a receptor, saturation of an iron-binding protein, or both.

In contrast to findings in iron deficiency, enhanced erythropoiesis, or hypoxia, endotoxin rapidly diminishes iron absorption without altering enterocyte iron concentration. This suggests that endotoxin and, perhaps, cytokines alter iron absorption by a different mechanism.

Most iron delivered to nonintestinal cells is bound to transferrin. Transferrin iron is delivered into nonintestinal cells via 2 pathways: the classical transferrin receptor pathway (high affinity, low capacity) and the pathway independent of the transferrin receptor (low affinity, high capacity). Otherwise, the nonsaturability of transferrin binding to cells cannot be explained.

In the classical transferrin pathway, the transferrin iron complex enters the cell within an endosome. Acidification of the endosome releases the iron from transferrin so that it can enter the cell. The apotransferrin is delivered by the endosome to the plasma for reutilization. The method by which the transferrin receptor–independent pathway delivers iron to the cell is not known.

Nonintestinal cells also possess the mobilferrin integrin and DMT-1 pathways. Their function in the absence of an iron-saturated transferrin is uncertain; however, their presence in nonintestinal cells suggests that they may participate in intracellular functions in addition to their capability to facilitate cellular uptake of iron.

Causes

Blood loss. Blood contains iron within red blood cells. So if you lose blood, you lose some iron. Women with heavy periods are at risk of iron deficiency anemia because they lose blood during menstruation. Slow, chronic blood loss within the body — such as from a peptic ulcer, a hiatal hernia, a colon polyp or colorectal cancer — can cause iron deficiency anemia. Gastrointestinal bleeding can result from regular use of some over-the-counter pain relievers, especially aspirin.

A lack of iron in your diet. Your body regularly gets iron from the foods you eat. If you consume too little iron, over time your body can become iron deficient. Examples of iron-rich foods include meat, eggs, leafy green vegetables and iron-fortified foods. For proper growth and development, infants and children need iron from their diet, too.

An inability to absorb iron. Iron from food is absorbed into your bloodstream in your small intestine. An intestinal disorder, such as celiac disease, which affects your intestine's ability to absorb nutrients from digested food, can lead to iron deficiency anemia. If part of your small intestine has been bypassed or removed surgically, that may affect your ability to absorb iron and other nutrients.

Pregnancy. Without iron supplementation, iron deficiency anemia occurs in many pregnant women because their iron stores need to serve their own increased blood volume as well as be a source of hemoglobin for the growing fetus.

Symptoms

Extreme fatigue Pale skin

Weakness

Shortness of breath

Headache

Dizziness or lightheadedness

Cold hands and feet

Irritability

Inflammation or soreness of your tongue

Brittle nails

Fast heartbeat

Unusual cravings for non-nutritive substances, such as ice, dirt or starch

Poor appetite, especially in infants and children with iron deficiency anemia

An uncomfortable tingling or crawling feeling in your legs (restless legs syndrome)

Exams and Tests

Endoscopy. Doctors often check for bleeding from a hiatal hernia, an ulcer or the stomach with the aid of endoscopy. In this procedure, a thin, lighted tube equipped with a video camera is passed down your throat to your stomach. This allows your doctor to view your esophagus — the tube that runs from your mouth to your stomach — and your stomach to look for sources of bleeding.

Colonoscopy. To rule out lower intestinal sources of bleeding, your doctor may recommend a procedure called colonoscopy. A thin, flexible tube equipped with a video camera is inserted into the rectum and guided to your colon. You're usually sedated during this test. A colonoscopy allows your doctor to view inside some or all of your colon and rectum to look for internal bleeding.

Ultrasound. Women may also have a pelvic ultrasound to look for the cause of excess menstrual bleeding, such as uterine fibroids.

Treatment

Iron supplements Your doctor may recommend iron tablets to replenish the iron stores in your body. To improve the chances that your body will absorb the iron in the tablets, you may be instructed to:

Take iron tablets on an empty stomach. If possible, take your iron tablets when your stomach is empty. However, because iron tablets can upset your stomach, you may need to take your iron tablets with meals.

Take iron tablets with vitamin C. Vitamin C improves the absorption of iron. Your doctor might recommend taking your iron tablets with a glass of orange juice or with a vitamin C supplement.

Iron supplements can cause constipation, so your doctor may also recommend a stool softener. Iron may turn your stools black, which is a harmless side effect.

Iron deficiency can't be corrected overnight. You may need to take iron supplements for several months or longer to replenish your iron reserves. Generally, you'll start to feel better after a week or so of treatment. Ask your doctor when you need to return to have your blood rechecked to measure your iron levels.

Treating underlying causes of iron deficiency If iron supplements don't increase your blood-iron levels, it's likely the anemia is due to a source of bleeding or an iron-absorption problem that your doctor will need to investigate and treat. Depending on the cause, iron deficiency anemia treatment may involve:

Medications, such as oral contraceptives to lighten heavy menstrual flow Antibiotics and other medications to treat peptic ulcers

Surgery to remove a bleeding polyp, a tumor or a fibroid

If iron deficiency anemia is severe, blood transfusions can help replace iron and hemoglobin quickly.

Vitamin Deficiency Anemia

Vitamin deficiency anemia is a lack of healthy red blood cells caused by lower-than-normal amounts of certain vitamins. The vitamins linked to vitamin deficiency anemia include folate, vitamin B-12 and vitamin C.

Vitamin deficiency anemia can occur if you don't eat enough folate, vitamin B-12 or vitamin C. Or vitamin deficiency anemia can occur if your body has trouble absorbing or processing these vitamins.

The lack of red blood cells caused by vitamin deficiency anemia can cause weakness and shortness of breath. Vitamin deficiency anemia can usually be corrected with vitamin supplements and changes to your diet.

Causes

Folate deficiency anemia. Folate, also known as vitamin B-9, is a nutrient found mainly in fruits and leafy green vegetables. A diet consistently lacking in these foods can lead to a deficiency.

An inability to absorb folate from food can also lead to a deficiency. Most nutrients from food are absorbed in your small intestine. People with diseases of the small intestine, such as Crohn's disease or celiac disease, or those who have had a large part of the small intestine surgically removed or bypassed, may have difficulty absorbing folate or its synthetic form, folic acid. Alcohol decreases absorption of folate, so drinking alcohol to excess may lead to a deficiency. Certain prescription drugs, such as some anti-seizure medications, can interfere with absorption of this nutrient.

Pregnant women and women who are breast-feeding have an increased demand for folate, as do people undergoing hemodialysis for kidney disease. Failure to meet this increased demand can result in a deficiency.

Vitamin B-12 deficiency anemia (pernicious anemia). Vitamin B-12 deficiency can result from a diet lacking in vitamin B-12, which is found mainly in meat, eggs and milk. Vitamin B-12 deficiency anemia can also occur if your small intestine can't absorb vitamin B-12. This may be due to surgery to your stomach or small intestine (such as gastric bypass surgery), abnormal bacterial growth in your small intestine, or an intestinal disease, such as Crohn's disease or celiac disease, that interferes with absorption of the vitamin. Vitamin B-12 deficiency can also be caused by a tapeworm ingested from contaminated fish, because the tapeworm saps nutrients from your body. However, a vitamin B-12 deficiency is most often due to a lack of a substance called intrinsic factor.

Intrinsic factor is a protein secreted by the stomach that joins vitamin B-12 in the stomach and escorts it through the small intestine to be absorbed by your bloodstream. Without intrinsic factor, vitamin B-12 can't be absorbed and leaves your body as waste. Lack of intrinsic factor may be due to an autoimmune reaction, in which your immune system mistakenly attacks the stomach cells that produce it. Vitamin B-12 deficiency anemia caused by a lack of intrinsic factor is called pernicious anemia.

Vitamin C deficiency anemia. Though rare, vitamin C deficiency can develop if you don't get enough vitamin C from the foods you eat. Vitamin C deficiency is also possible if something impairs your ability to absorb vitamin C from food. For instance, smoking impairs your body's ability to absorb vitamin C.

Symptoms

Fatigue Shortness of breath

Dizziness

Pale or yellowish skin

Swollen tongue that may appear dark red

Weight loss

Diarrhea

Numbness or tingling in your hands and feet

Muscle weakness

Irritability

Unsteady movements

Mental confusion or forgetfulness

Vitamin deficiencies usually develop slowly over several months to years. Vitamin deficiency symptoms may be subtle at first, but they increase as the deficiency worsens.

Exams and Tests

Doctors diagnose vitamin deficiency anemias through blood tests that check:

The number and appearance of red blood cells. People with anemia have fewer red blood cells than normal. In vitamin deficiency anemias related to a lack of vitamin B-12 and folate, the red blood cells appear large and underdeveloped. In advanced deficiencies, white blood cells and platelets also look abnormal under a microscope.

The amount of folate, vitamin B-12 and vitamin C in your blood. Folate and vitamin B-12 levels are measured at the same time, because these deficiencies can cause similar signs and symptoms.

Additional tests for B-12 deficiency If blood tests reveal a vitamin deficiency, your doctor may perform other tests to determine the type and cause, such as:

Antibodies test. Your doctor may draw a sample of your blood to check for antibodies to intrinsic factor. Their presence indicates pernicious anemia.

Methylmalonic acid test. You may undergo a blood test to measure the presence of a substance called methylmalonic acid. The level of this substance is higher in people with vitamin B-12 deficiency.

Schilling test. In this test, you first ingest a tiny amount of radioactive vitamin B-12. Then your blood is checked to see if your body absorbed the vitamin B-12. After that, you ingest a combination of radioactive vitamin B-12 and intrinsic factor. If the radioactive B-12 is absorbed only when taken with intrinsic factor, it confirms that you lack your own intrinsic factor.

Treatment

Treatment for vitamin deficiency anemia includes supplements and changes in diet.

Folate deficiency anemia. Treatment involves eating a healthy diet and taking folic acid supplements as prescribed by your doctor. In most cases, folic acid supplements are taken orally. Once your body's level of folate increases to normal, you may be able to stop taking the supplements. But if the cause of your folate deficiency can't be corrected, you may need to take folic acid supplements for life.

Vitamin B-12 deficiency anemia (pernicious anemia). For milder cases of vitamin B-12 deficiency, treatment may involve changes to your diet and vitamin B-12 supplements in pill form or as a nasal spray. In more severe cases, you may receive vitamin B-12 injections. At first you may receive the shots as often as every other day. Eventually you'll need injections just once a month, which may continue for life, depending on your situation.

Vitamin C deficiency anemia. Treatment for anemia related to vitamin C deficiency is with vitamin C tablets. Additionally, you increase your intake of foods and beverages that contain vitamin C.

Hemolytic Anemia

An anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs) either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular). It has numerous possible causes, ranging from relatively harmless to life-threatening. The general classification of hemolytic anemia is either inherited or acquired. Treatment depends on the cause and nature of the breakdown.

Pathophysiology

Hemolysis is the final event triggered by a large number of hereditary and acquired disorders. The etiology of premature erythrocyte destruction is diverse and can be due to conditions such as intrinsic membrane defects, abnormal hemoglobins, erythrocyte enzymatic defects, immune destruction of erythrocytes, mechanical injury, and hypersplenism.

Hemolysis may be an extravascular or an intravascular phenomenon. Autoimmune hemolytic anemia and hereditary spherocytosis are classified as examples of extravascular hemolysis because the red blood cells are destroyed in the spleen and other reticuloendothelial organs.[1] Intravascular hemolysis occurs in hemolytic anemia due to prosthetic cardiac valves, G-6-PD deficiency, thrombotic

thrombocytopenic purpura, disseminated intravascular coagulation, and paroxysmal nocturnal hemoglobinuria (PNH).

Hemolysis is associated with a release of hemoglobin and lactic acid dehydrogenase (LDH). An increase in indirect bilirubin and urobilinogen is derived from released hemoglobin.

A patient with mild hemolysis may have normal hemoglobin levels if increased production matches the rate of erythrocyte destruction. Alternatively, patients with mild hemolysis may experience marked anemia if their bone marrow erythrocyte production is transiently shut off by viral (parvovirus B19) or other infections, resulting in uncompensated destruction of erythrocytes (aplastic hemolytic crisis, in which a decrease in the erythrocytes occurs in a patient with ongoing hemolysis).

Skull and skeletal deformities can occur with a marked increase in hematopoiesis, expansion of bone in infancy, and early childhood disorders such as sickle cell anemia or thalassemia.

Causes

The defect may be in the red blood cell itself (intrinsic factors), or outside the red blood cell (extrinsic factors).

Intrinsic factors are often present at birth (hereditary). They include:

Abnormalities in the proteins that build normal red blood cells Differences in the protein inside a red blood cell that carries oxygen (hemoglobin)

Extrinsic factors include:

Abnormal immune system responses Blood clots in small blood vessels

Certain infections

Side effects from medications

Symptoms

Chills Dark urine

Enlarged spleen

Fatigue

Fever

Pale  skin color (pallor)

Rapid heart rate

Shortness of breath

Yellow skin color  (jaundice)

Exams and Tests

Absolute reticulocyte count Free hemoglobin in the serum or urine

Hemosiderin in the urine

Red blood cell count  (RBC), hemoglobin, and hematocrit (HCT)

Serum haptoglobin  levels

Serum indirect bilirubin levels

Serum LDH

Urine and fecal urobilinogen

Treatment

Treatment depends on the type and cause of the hemolytic anemia. Folic acid, iron replacement, and corticosteroids may be used. In emergencies, a blood transfusion or removal of the spleen (splenectomy) may be necessary.

Lead poisoning

Lead poisoning (also known as plumbism, colica Pictonum, saturnism, Devon colic, or painter's colic) is a medical condition caused by increased levels of the heavy metal lead in the body. Lead interferes with a variety of body processes and is toxic to many organs and tissues including the heart, bones, intestines, kidneys, and reproductive and nervous systems. It interferes with the development of the nervous system and is therefore particularly toxic to children, causing potentially permanent learning and behavior disorders. Symptoms include abdominal pain, confusion, headache, anemia, irritability, and in severe cases seizures, coma, and death.

Causes

Lead in paint The use of lead-based paints for homes, children's toys and household furniture has been banned in the United States since 1978. But lead-based paint is still on walls and woodwork in many older homes and apartments. Most lead poisoning in children results from eating lead-based paint chips.

Water pipes and imported canned goods Lead pipes, brass plumbing fixtures and copper pipes soldered with lead can release lead particles into tap water. Although lead solder in food cans is banned in the United States, it's still used in some countries.

Traditional remedies Some cases of lead poisoning have been traced to the use of certain traditional medicines, including:

Greta or azarcon. This fine orange powder — also known as alarcon, coral, luiga, maria luisa or rueda — is a Hispanic remedy taken for an upset stomach, constipation, diarrhea and vomiting. It's also used to soothe teething babies.

Litargirio. Also known as litharge, this peach-colored powder is used as a deodorant, especially in the Dominican Republic.

Ba-baw-san. This Chinese herbal remedy is used to treat colic pain in babies.

Ghasard. A brown powder, ghasard is used as a tonic in India.

Daw tway. A digestive aid used in Thailand, daw tway contains high levels of lead and arsenic.

Other sources of lead exposure Lead can also sometimes be found in:

Soil. Lead particles that settle on the soil from leaded gasoline or paint can last for years. Lead-contaminated soil is still a major problem around highways and in some urban settings.

Household dust. Household dust can contain lead from lead paint chips or from contaminated soil brought in from outside.

Pottery. Glazes found on some ceramics, china and porcelain can contain lead that may leach into food.

Toys. Lead is sometimes found in toys and other products produced abroad.

Traditional cosmetics. Kohl is a traditional cosmetic, often used as eyeliner. Testing of various samples of kohl has revealed high levels of lead.

Symptoms

Symptoms in children The signs and symptoms of lead poisoning in children may include:

Irritability

Loss of appetite

Weight loss

Sluggishness and fatigue

Abdominal pain

Vomiting

Constipation

Learning difficulties

Symptoms in newborns Babies who are exposed to lead before birth may experience:

Learning difficulties

Slowed growth

Symptoms in adults Although children are primarily at risk, lead poisoning is also dangerous for adults. Signs and symptoms in adults may include:

High blood pressure

Declines in mental functioning

Pain, numbness or tingling of the extremities

Muscular weakness

Headache

Abdominal pain

Memory loss

Mood disorders

Reduced sperm count, abnormal sperm

Miscarriage or premature birth in pregnant women

Exams and Tests

Doctors usually use a simple blood test to detect lead poisoning. A small blood sample is taken from a finger prick or from a vein. Lead levels in the blood are measured in micrograms per deciliter (mcg/dL). An unsafe level is 10 mcg/dL or higher.

Treatment

The first step in treating all degrees of lead poisoning is to remove the source of the contamination. If you can't remove lead from your environment, you may at least be able to reduce the likelihood that it will cause problems. For instance, sometimes it might be better to seal in, rather than remove, old lead paint. Your local health department can recommend ways to identify and reduce lead in your home and community.

For children and adults with relatively low lead levels, simply avoiding exposure to lead may be enough to reduce blood lead levels.

Treating higher levels For more-severe cases, your doctor may recommend:

Chelation therapy. In this treatment, you take a medication that binds with the lead so that it's excreted in your urine.

EDTA therapy. Doctors treat lead levels greater than 45 mcg/dL of blood with a chemical called ethylenediaminetetraacetic acid (EDTA). Depending on your lead level, you may need more than one treatment. In such severe cases, however, it may not be possible to reverse damage that has already occurred.

Autoimmune hemolytic anemia

Autoimmune hemolytic anemia is a type of hemolytic anemia where the body's immune system attacks its own red blood cells (RBCs), leading to their destruction (hemolysis). Types of AIHA include Warm autoimmune hemolytic anemia, Cold agglutinin disease, and Paroxysmal cold hemoglobinuria.

Causes

The cause is unknown. Autoimmune hemolytic anemia accounts for one-half of all immune hemolytic anemias.

There are other types of immune hemolytic anemias in which the cause may result from an underlying disease or medication. The disease may start quickly and be very serious.

Risk factors are not known.

Symptoms

Dark urine Fatigue

Pale  color (pallor)

Rapid heartbeat

Shortness of breath

Yellow skin color  (jaundice)

Exams and Tests

An examination may reveal an enlarged spleen.

Tests include:

Direct Coombs' test Hemoglobin  in the urine

Indirect Coombs' test

Red blood cell count  and serum hemoglobin

Reticulocyte count

Serum bilirubin levels

Serum haptoglobin

Treatment

An examination may reveal an enlarged spleen.

Tests include:

Direct Coombs' test Hemoglobin  in the urine

Indirect Coombs' test

Red blood cell count  and serum hemoglobin

Reticulocyte count

Serum bilirubin levels

Serum haptoglobin

Sickle cell anemia

Sickle cell anemia is an inherited form of anemia — a condition in which there aren't enough healthy red blood cells to carry adequate oxygen throughout your body.

Normally, your red blood cells are flexible and round, moving easily through your blood vessels. In sickle cell anemia, the red blood cells become rigid and sticky and are shaped like sickles or crescent moons. These irregularly shaped cells can get stuck in small blood vessels, which can slow or block blood flow and oxygen to parts of the body.

There's no cure for most people with sickle cell anemia. However, treatments can relieve pain and help prevent further problems associated with sickle cell anemia.

Pathophysiology

HbS arises from a mutation substituting thymine for adenine in the sixth codon of the beta-chain gene, GAG to GTG. This causes coding of valine instead of glutamate in position 6 of the Hb beta chain. The resulting Hb has the physical properties of forming polymers under deoxy conditions. It also exhibits

changes in solubility and molecular stability. These properties are responsible for the profound clinical expressions of the sickling syndromes.

Under deoxy conditions, HbS undergoes marked decrease in solubility, increased viscosity, and polymer formation at concentrations exceeding 30 g/dL. It forms a gel-like substance containing Hb crystals called tactoids. The gel-like form of Hb is in equilibrium with its liquid-soluble form. A number of factors influence this equilibrium, including oxygen tension, concentration of Hb S, and the presence of other hemoglobins.

Oxygen tension is a factor in that polymer formation occurs only in the deoxy state. If oxygen is present, the liquid state prevails. Concentration of Hb S is a factor in that gelation of HbS occurs at concentrations greater than 20.8 g/dL (the normal cellular Hb concentration is 30 g/dL). The presence of other hemoglobins is a factor in that normal adult hemoglobin (HbA) and fetal hemoglobin (HbF) have an inhibitory effect on gelation.

These and other Hb interactions affect the severity of clinical syndromes. HbSS produces a more severe disease than sickle cell HbC (HbSC), HbSD, HbSO Arab, and Hb with one normal and one sickle allele (HbSA).

When red blood cells (RBCs) containing homozygous HbS are exposed to deoxy conditions, the sickling process begins. A slow and gradual polymer formation ensues. Electron microscopy reveals a parallel array of filaments. Repeated and prolonged sickling involves the membrane; the RBC assumes the characteristic sickled shape.

Causes

Sickle cell anemia is caused by a mutation in the gene that tells your body to make hemoglobin — the red, iron-rich compound that gives blood its red color. Hemoglobin allows red blood cells to carry oxygen from your lungs to all parts of your body. In sickle cell anemia, the abnormal hemoglobin causes red blood cells to become rigid, sticky and misshapen.

The sickle cell gene is passed from generation to generation in a pattern of inheritance called autosomal recessive inheritance. This means that both the mother and the father must pass on the defective form of the gene for a child to be affected.

If only one parent passes the sickle cell gene to the child, that child will have the sickle cell trait. With one normal hemoglobin gene and one defective form of the gene, people with the sickle cell trait make both normal hemoglobin and sickle cell hemoglobin. Their blood may contain some sickle cells, but they generally don't experience symptoms. However, they are carriers of the disease, which means they can pass the defective gene on to their children.

With each pregnancy, two people with sickle cell traits have:

A 25 percent chance of having an unaffected child with normal hemoglobin

A 50 percent chance of having a child who also is a carrier

A 25 percent chance of having a child with sickle cell anemia

Symptoms

Signs and symptoms of sickle cell anemia usually show up after an infant is 4 months old and may include:

Anemia. Sickle cells are fragile. They break apart easily and die, leaving you chronically short on red blood cells. Red blood cells usually live for about 120 days before they die and need to be replaced. However, sickle cells die after only 10 to 20 days. The result is a chronic shortage of red blood cells, known as anemia. Without enough red blood cells in circulation, your body can't get the oxygen it needs to feel energized. That's why anemia causes fatigue.

Episodes of pain. Periodic episodes of pain, called crises, are a major symptom of sickle cell anemia. Pain develops when sickle-shaped red blood cells block blood flow through tiny blood vessels to your chest, abdomen and joints. Pain can also occur in your bones. The pain may vary in intensity and can last for a few hours to a few weeks. Some people experience only a few episodes of pain. Others experience a dozen or more crises a year. If a crisis is severe enough, you may need to be hospitalized.

Hand-foot syndrome. Swollen hands and feet may be the first signs of sickle cell anemia in babies. The swelling is caused by sickle-shaped red blood cells blocking blood flow out of their hands and feet.

Frequent infections. Sickle cells can damage your spleen, an organ that fights infection. This may make you more vulnerable to infections. Doctors commonly give infants and children with sickle cell anemia antibiotics to prevent potentially life-threatening infections, such as pneumonia.

Delayed growth. Red blood cells provide your body with the oxygen and nutrients you need for growth. A shortage of healthy red blood cells can slow growth in infants and children and delay puberty in teenagers.

Vision problems. Some people with sickle cell anemia experience vision problems. Tiny blood vessels that supply your eyes may become plugged with sickle cells. This can damage the retina — the portion of the eye that processes visual images.

When to see a doctorAlthough sickle cell anemia is usually diagnosed in infancy, if you or your child develops any of the following problems, see your doctor right away or seek emergency medical care:

Unexplained episodes of severe pain, such as pain in abdomen, chest, bones or joints.

Swelling in the hands or feet.

Abdominal swelling, especially if the area is tender to touch.

Fever. People with sickle cell anemia have an increased risk of infection, and fever can be the first sign of an illness.

Pale skin or nail beds.

Yellow tint to the skin or the whites of the eyes.

Any signs or symptoms of stroke. If you notice any one-sided paralysis or weakness in the face, arms or legs, confusion, trouble walking or talking, sudden vision problems or numbness, or a headache, call 911 or your local emergency number right away.

Exams and Tests

A blood test can check for hemoglobin S — the defective form of hemoglobin that underlies sickle cell anemia. In the United States, this blood test is part of routine newborn screening done at the hospital. But older children and adults can be tested, too.

In adults, a blood sample is drawn from a vein in the arm. In young children and babies, the blood sample is usually collected from a finger or heel. The sample is then sent to a laboratory, where it's screened for hemoglobin S.

If the screening test is negative, there is no sickle cell gene present. If the screening test is positive, further tests will be done to determine whether one or two sickle cell genes are present. People who have one gene — sickle cell trait — have a fairly small percentage of hemoglobin S. People with two genes — sickle cell disease — have a much larger percentage of the defective hemoglobin.

Additional testsTo confirm any diagnosis, a sample of blood is examined under a microscope to check for large numbers of sickle cells — a marker of the disease. If you or your child has the disease, a blood test to check for anemia — a low red blood cell count — will be done. And your doctor may suggest additional tests to check for possible complications of the disease.

If you or your child carries the sickle cell gene, you may be referred to a genetic counselor — an expert in genetic diseases.

Tests to detect sickle cell genes before birthSickle cell anemia can be diagnosed in an unborn baby by sampling some of the fluid surrounding the baby in the mother's womb (amniotic fluid) to look for the sickle cell gene. If you or your partner has been diagnosed with sickle cell anemia or sickle cell trait, ask your doctor about whether you should consider this screening. Ask for a referral to a genetic counselor who can help you understand the risk to your baby.

Treatment

Bone marrow transplant offers the only potential cure for sickle cell anemia. But, finding a donor is difficult and the procedure has serious risks associated with it, including death.

As a result, treatment for sickle cell anemia is usually aimed at avoiding crises, relieving symptoms and preventing complications. If you have sickle cell anemia, you'll need to make regular visits to your doctor to check your red blood cell count and monitor your health. Treatments may include medications to reduce pain and prevent complications, blood transfusions and supplemental oxygen, as well as bone marrow transplant.

MedicationsMedications used to treat sickle cell anemia include:

Antibiotics. Children with sickle cell anemia may begin taking the antibiotic penicillin when they're about 2 months of age and continue taking it until they're 5 years old. Doing so helps prevent infections, such as pneumonia, which can be life-threatening to an infant or child with sickle cell anemia. Antibiotics may also help adults with sickle cell anemia fight certain infections.

Pain-relieving medications. To relieve pain during a sickle crisis, your doctor may advise over-the-counter pain relievers and application of heat to the affected area. You may also need stronger prescription pain medication.

Hydroxyurea (Droxia, Hydrea). When taken daily, hydroxyurea reduces the frequency of painful crises and may reduce the need for blood transfusions. It may be an option for adults with

severe disease. Hydroxyurea seems to work by stimulating production of fetal hemoglobin — a type of hemoglobin found in newborns that helps prevent the formation of sickle cells. Hydroxyurea increases your risk of infections, and there is some concern that long-term use of this drug may cause tumors or leukemia in certain people. Your doctor can help you determine if this drug may be beneficial for you.

Assessing stroke riskUsing a special ultrasound machine (transcranial), doctors can learn which children have a higher risk of stroke. This test can be used on children as young as 2, and those who are found to have a high risk of stroke are then treated with regular blood transfusions.

Immunizations to prevent infectionsBecause infections can be very serious in children with sickle cell anemia, your doctor will likely recommend your child receive the available vaccinations.

Blood transfusionsIn a red blood cell transfusion, red blood cells are removed from a supply of donated blood. These donated cells are then given intravenously to a person with sickle cell anemia.

Blood transfusions increase the number of normal red blood cells in circulation, helping to relieve anemia. In children with sickle cell anemia at high risk of stroke, regular blood transfusions can decrease their risk of stroke.

Blood transfusions carry some risk. Blood contains iron. Regular blood transfusions cause an excess amount of iron to build up in your body. Because excess iron can damage your heart, liver and other organs, people who undergo regular transfusions may need treatment to reduce iron levels. Deferasirox (Exjade) is an oral medication that can reduce excess iron levels.

Supplemental oxygenBreathing supplemental oxygen through a breathing mask adds oxygen to your blood and helps you breathe easier. It may be helpful if you have acute chest syndrome or a sickle cell crisis.

Stem cell transplantA stem cell transplant, also called a bone marrow transplant, involves replacing bone marrow affected by sickle cell anemia with healthy bone marrow from a donor. A stem cell transplant is recommended only for people who have significant symptoms and problems from sickle cell anemia.

If a donor is found, the diseased bone marrow in the person with sickle cell anemia is first depleted with radiation or chemotherapy. Healthy stem cells from the donor are filtered from the blood. The healthy stem cells are injected intravenously into the bloodstream of the person with sickle cell anemia, where they migrate to the bone marrow cavities and begin generating new blood cells. The procedure requires a lengthy hospital stay. After the transplant, you'll receive drugs to help prevent rejection of the donated stem cells.

A stem cell transplant carries risks. There's a chance that your body may reject the transplant, leading to life-threatening complications. In addition, not everyone is a candidate for transplantation or can find a suitable donor.

Treating complicationsDoctors treat most complications of sickle cell anemia as they occur. Treatment may include antibiotics, vitamins, blood transfusions, pain-relieving medicines, other medications and possibly surgery, such as to correct vision problems or to remove a damaged spleen.

Experimental treatmentsScientists are studying new treatments for sickle cell anemia, including:

Gene therapy. Because sickle cell anemia is caused by a defective gene, researchers are exploring whether inserting a normal gene into the bone marrow of people with sickle cell anemia will result in the production of normal hemoglobin. Scientists are also exploring the possibility of turning off the defective gene while reactivating another gene responsible for the production of fetal hemoglobin — a type of hemoglobin found in newborns that prevents sickle cells from forming.

Nitric oxide. People with sickle cell anemia have low levels of nitric oxide in their blood. Nitric oxide is a gas that helps keep blood vessels open and reduces the stickiness of red blood cells. Treatment with nitric oxide may prevent sickle cells from clumping together.

Drugs to boost fetal hemoglobin production. Researchers are studying various drugs to devise a way to boost the production of fetal hemoglobin. This is a type of hemoglobin that stops sickle cells from forming.

Diseases of the Pituitary Gland

Growth Hormone Deficiency

Growth Hormone Deficiency (GHD) is a medical condition in which the body does not produce enough growth hormone (GH). Growth hormone, also called somatotropin, is a polypeptide hormone which stimulates growth and cell reproduction. HGH also refers to human growth hormone but this older abbreviation has begun to develop paradoxical connotations, particularly in relation to the peddling of medically unnecessary GH supplementation

Causes

Growth hormone deficiency is caused by low or absent secretion of growth hormone from the pituitary gland. This can be caused by congenital (a condition that is present at birth) or acquired (a condition that occurs after birth) conditions. Congenital growth hormone deficiency may be associated with an abnormal pituitary gland, or it may be part of another syndrome. In normal aging, there is a decrease in the amount of growth hormone secreted each day and in the pattern of secretion. It is not clear if this is clinically important or requires any additional administration. Acquired causes of growth hormone deficiency include infections; brain tumors; and injury, surgery, or radiation to the head. In some cases, no causes can be identified.

Pathophysiology

Growth hormone promotes linear growth by regulating the endocrine and paracrine production of insulinlike growth factor 1 (IGF-1), which is produced by the liver and other target tissues, including the epiphyseal growth plate. Growth hormone's diverse metabolic actions also include anabolic, lipolytic, and diabetogenic effects.

GHD results in alterations in the physiology of different systems of the body, manifesting in increased subcutaneous visceral fat and decreased muscle mass, bone density, and exercise performance.

Symptoms

Symptoms of GH deficiency in children include the following: 

Short stature

Low growth velocity (speed) for age and pubertal stage

Increased amount of fat around the waist

The child may look younger than other children his or her age

Delayed tooth development

Delayed onset of puberty

Symptoms of GH deficiency in adults include the following: 

Low energy

Decreased strength and exercise tolerance

Decreased muscle mass

Weight gain, especially around the waist

Feelings of anxiety, depression, or sadness causing a change in social behavior

Thin and dry skin

Exams and Tests

To determine if growth hormone deficiency is present, a growth hormone stimulation test may be performed. 

This test involves injecting insulin (hormone that regulates blood sugar levels) through an IV to produce a low plasma glucose (a sugar) level. The peak growth hormone level is measured 20-30 minutes later.

If the peak growth hormone level is less than 10 mcg/mL in children or less than 3 mcg/mL in adults, growth hormone deficiency is diagnosed.

Persons with growth hormone deficiency may have increased total cholesterol, low-densitylipoprotein (LDL) cholesterol, apolipoprotein B, and triglyceride levels. 

Other tests that may be performed include a CT scan and/or MRI of the brain and/or bones. Images from these tests may reveal tumors. Reduced bone density can be evaluated by a DEXA or bone density scan.

Treatment

Children and some adults with growth hormone deficiency will benefit from growth hormone therapy. The goals of treatment are to increase growth in children and restore energy,metabolism, and body composition. The doctor may prescribe growth hormone, also called somatropin (Humatrope, Genotropin). The drug is given as shots a few times a week that is injected underneath the fat of the patient’s skin.

Hypopituitarism

Hypopituitarism is the decreased (hypo) secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of most pituitary hormones, the term panhypopituitarism (pan meaning "all") is used.

Pathophysiology

When pituitary hormone production is impaired, target gland hormone production is reduced because of a lack of trophic stimulus. Normally, subphysiologic target hormone levels stimulate the pituitary gland to increase trophic hormone production; however, in hypopituitarism, the pituitary gland response is absent, suboptimal, or inappropriate with biologically inert hormone production. This results in progressive secondary failure of the target glands. Patients with hypopituitarism typically present with low target hormone levels accompanied by low levels of the corresponding trophic hormone.

The trophic hormone level may appear to be within the reference range with a corresponding subphysiologic target hormone level. Such a trophic hormone level would be inappropriately low for the subphysiologic target hormone level. Sometimes, the assayed trophic hormone level may be biologically inert.

Causes

Hypopituitarism is frequently triggered by a tumor of the pituitary gland. As a pituitary tumor increases in size, it can compress and damage pituitary tissue, interfering with hormone production. A tumor can also compress the optic nerves, causing visual disturbances.

The cause of hypopituitarism can also be other diseases and events that damage the pituitary, such as:

Head injuries

Brain tumor

Brain surgery

Radiation treatment

Autoimmune inflammation (hypophysitis)

Stroke

Infections of the brain, such as meningitis

Tuberculosis

Infiltrative diseases, such as sarcoidosis, which is an inflammatory disease occurring in various organs; histiocytosis X, in which abnormal cells cause scarring in numerous parts of the body, such as the lungs and bones; and hemochromatosis, which causes excess iron deposition in the liver and other tissues

Severe loss of blood during childbirth, which may cause damage to the front part of the pituitary gland (Sheehan syndrome, or postpartum hypopituitarism)

Genetic mutations resulting in impaired pituitary hormone production

Diseases of the hypothalamus, a portion of the brain situated just above the pituitary, also can cause hypopituitarism. The hypothalamus produces hormones of its own that directly affect the activity of the pituitary.

In some cases, the cause of hypopituitarism is unknown.

Symptoms

Hypopituitarism is often progressive. Although the signs and symptoms can occur suddenly, they more often develop gradually. They are sometimes subtle and may be overlooked for months or even years.

Signs and symptoms of hypopituitarism vary, depending on which pituitary hormones are deficient and how severe the deficiency is. They may include:

Fatigue

Weight loss

Decreased sex drive

Sensitivity to cold or difficulty staying warm

Decreased appetite

Facial puffiness

Anemia

Infertility

Hot flashes, irregular or no periods, loss of pubic hair, and inability to produce milk for breast-feeding in women

Decreased facial or body hair in men

Short stature in children

Exams and Tests

Tests your doctor may order include:

Blood tests. They can help detect deficits in hormones as a result of pituitary failure. For example, blood tests can identify low levels of thyroid, adrenal or sex hormones, and can determine if these low levels are associated with inadequate pituitary hormone production.

Stimulation or dynamic testing. Your doctor may suggest you go to a specialized endocrine clinic for these tests, which check your body's secretion of hormones after you've taken certain medications that can stimulate hormone production.

Brain imaging. A computerized tomography (CT) or magnetic resonance imaging (MRI) scan of your brain can detect a pituitary tumor or other structural abnormality.

Vision tests. These tests can determine if growth of a pituitary tumor has impaired your sight or visual fields.

X-ray. In children, an X-ray of the hand and wrist can measure whether the bones are growing normally.

Treatment

Corticosteroids. These drugs, such as hydrocortisone or prednisone, replace the adrenal hormones that aren't being produced because of an adrenocorticotropic hormone (ACTH) deficiency. You take them by mouth.

Levothyroxine (Levoxyl, Synthroid, others). This medication replaces deficient thyroid hormone levels caused by low or deficient TSH production.

Sex hormones. These include testosterone in men and estrogen or a combination of estrogen and progesterone in women. Testosterone is administered through the skin with either a patch or a gel or by injection. Female hormone replacement can be administered with either pills or patches.

Desmopressin (DDAVP). You take this hormone to replace ADH and to reduce your body's loss of water through frequent urination. Desmopressin is taken as a nasal spray or oral tablet or by injection.

Growth hormone. Also called somatropin, growth hormone is taken through an injection beneath your skin. It promotes growth, thus producing more normal height in children. Adults with a growth hormone deficiency also may benefit from growth hormone replacement, but they won't become taller.

Acromegaly

Acromegaly (pronounced /ˌækrɵˈmɛɡəli/; from Greek άκρος akros "extreme" or "extremities" and μεγάλος megalos "large") is asyndrome that results when the anterior pituitary gland produces excess growth hormone (hGH) after epiphyseal plate closure at puberty. A number of disorders may increase the pituitary's GH output, although most commonly it involves a GH producing tumor called pituitary adenoma, derived from a distinct type of cell (somatotrophs).

Acromegaly most commonly affects adults in middle age,[1] and can result in severe disfigurement, serious complicating conditions, and premature death if unchecked. Because of its insidious pathogenesis and slow progression, the disease is hard to diagnose in the early stages and is frequently missed for many years, until changes in external features, especially of the face, become noticeable.

Pathophysiology

GH secreted from the anterior pituitary somatotrophs is normally controlled by 2 hypothalamic factors.

1. GHRH stimulates GH secretion and synthesis and is synthesized in the hypothalamus and transported via the hypothalamic pituitary portal system to the somatotrophs of the anterior pituitary.

2. Several tissues, including the endocrine pancreas, produce somatostatin in response to GH. Somatostatin inhibits GHRH secretion in a negative feedback pathway.

Once released into circulation, GH stimulates the production of insulinlike growth factor-I (IGF-I), also known as somatomedin C (SM-C). The main source of circulating IGF-I is the liver, though it is produced in many other tissues. IGF-I is the primary mediator of the growth-promoting effects of GH.

More than 95% of acromegaly cases are caused by a pituitary adenoma that secretes excess amounts of GH. Ectopic production of GH and GHRH by malignant tumors accounts for other causes.

Of these tumors, up to 40% have a mutation involving the alpha subunit of the stimulatory guanosine triphosphate (GTP)–binding protein. In the presence of a mutation, persistent elevation of cyclic adenosine monophosphate (cAMP) in the somatotrophs results in excessive GH secretion.

The pathologic effects of GH excess include acral overgrowth (ie, macrognathia; enlargement of the facial bone structure; enlarged hands and feet; visceral overgrowth, including macroglossia and enlarged heart muscle, thyroid, liver, kidney), insulin antagonism, nitrogen retention, and increased risk of colon polyps/tumors.

The role of genetic mutations was highlighted in a report suggesting that patients with pituitary tumors from 4 Irish families share a common mutation with a patient from the 18th century who had pituitary tumor–mediated gigantism.

Causes

In adults, a tumor is the most common cause of excess growth hormone:

Pituitary tumors. Most cases of acromegaly are caused by a noncancerous (benign) tumor, or adenoma, of the pituitary gland. In addition to producing excess growth hormone, these tumors can press on nearby tissues as they grow. This pressure can cause some of the symptoms of acromegaly, such as headaches and impaired vision.

Nonpituitary tumors. In a few people, acromegaly is caused by benign or cancerous tumors in other parts of the body, such as the lungs, pancreas or adrenal glands. Some of these tumors actually secrete growth hormone. In other cases, they produce a hormone called growth hormone-releasing hormone (GH-RH), which stimulates the pituitary gland to make more growth hormone.

Symptoms

Typical signs and symptoms of acromegaly include:

Enlarged hands and feet

Larger and broader facial features

Protrusion of the lower jaw so the lower teeth extend beyond the upper teeth (underbite)

Thickened, oily skin

Excessive sweating and body odor

Small skin outgrowths (skin tags)

Fatigue and muscle weakness

A deepened, husky voice due to enlarged vocal cords and sinuses

Severe snoring and frequent brief interruptions in nighttime breathing (sleep apnea) due to tissue swelling that blocks your upper airway

Impaired vision

Headaches

Enlarged tongue

Back pain

Pain and limited mobility in joints

Menstrual cycle irregularities in women

Reduced sex drive and, in men, trouble achieving or maintaining an erection (erectile dysfunction)

Enlarged liver, heart, kidneys, spleen and other organs

Increased chest size (barrel chest)

Exams and Tests

Measuring IGF-1. Because growth hormone stimulates your liver to produce IGF-1 — another growth hormone — IGF-1 blood levels are nearly always elevated when you have acromegaly.

Measuring growth hormone before and after you drink glucose.Your doctor may also test your growth hormone levels to confirm that you have acromegaly. In this test, your blood levels of growth hormone are measured both before and at several points after you drink a preparation of sugar (glucose). Normally, taking in glucose causes growth hormone levels to fall. But if your body is producing too much growth hormone, levels stay high.

Imaging. After acromegaly has been diagnosed by measuring your IGF-1 and growth hormone levels, your doctor will likely recommend magnetic resonance imaging (MRI) of your brain to pinpoint the size and location of your tumor. Brain imaging may sometimes be performed with computerized tomography (CT). If brain imaging fails to detect a pituitary tumor, your doctor may recommend additional blood work and further imaging studies of your chest or abdomen.

Gigantism

Gigantism, also known as giantism (from Greek gigas, gigantas "giant"), is a condition characterized by excessive growth and height significantly above average. In humans, this condition is caused by over-production of growth hormone.

Pathophysiology

Causes of excess IGF-I action may be divided into 3 categories: (1) those originating from primary GH excess released from the pituitary; (2) those caused by increased GH-releasing hormone (GHRH) secretion or hypothalamic dysregulation; and (3) hypothetically, those related to the excessive production of IGF-binding protein, which prolongs the half-life of circulating IGF-I.

By far, most people with giantism have GH-secreting pituitary adenomas or hyperplasia. Although gigantism is typically an isolated disorder, rare cases occur as a feature of other conditions, such

as multiple endocrine neoplasia (MEN) type I, McCune-Albright syndrome (MAS), neurofibromatosis, tuberous sclerosis, or Carney complex.

Approximately 20% of patients with gigantism have MAS (the triad of precocious puberty, café au lait spots, fibrous dysplasia) and may have either pituitary hyperplasia or adenomas.

Causes

The most common cause of too much growth hormone release is a noncancerous (benign) tumor of the pituitary gland. Other causes include:

Carney complex McCune-Albright syndrome  (MAS)

Multiple endocrine neoplasia type 1  (MEN-1)

Neurofibromatosis

If excess growth hormone occurs after normal bone growth has stopped, the condition is known as acromegaly.

Gigantism is very rare.

Symptoms

The child will grow in height, as well as in the muscles and organs. This excessive growth makes the child extremely large for his or her age.

Other symptoms include:

Delayed puberty Double vision or difficulty with side (peripheral) vision

Frontal bossing  and a prominent jaw

Headache

Increased sweating

Irregular periods (menstruation)

Large hands and feet with thick fingers and toes

Release of breast milk

Thickening of the facial features

Weakness

Exams and Tests

CT  or MRI scan of the head showing pituitary tumor

Failure to suppress serum growth hormone (GH) levels after an oral glucose challenge (maximum 75g)

High prolactin levels

Increased insulin growth factor-I (IGF-I) levels

Damage to the pituitary may lead to low levels of other hormones, including:

Cortisol Estradiol  (girls)

Testosterone  (boys)

Thyroid hormone

Treatment

In pituitary tumors with well-defined borders, surgery is the treatment of choice and can cure many cases.

For situations in which surgery cannot completely remove the tumor, medication is the treatment of choice. The most effective medications are somatostatin analogs (such as octreotide or long-acting lanreotide), which reduce growth hormone release.

Dopamine agonists (bromocriptine mesylate, cabergoline) have also been used to reduce growth hormone release, but these are generally less effective. Pegvisomant, a medication that blocks the effect of growth hormone, may be used.

Radiation therapy has also been used to bring growth hormone levels to normal. However, it can take 5 - 10 years for the full effects to be seen and almost always leads to low levels of other pituitary hormones.

Radiation has also been linked to learning disabilities, obesity, and emotional changes in children. Most experts will use radiation only if surgery and medication fail.

Cushing’s Syndrome

Cushing's syndrome is a hormone disorder caused by high levels of cortisol in the blood. This can be caused by takingglucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone (ACTH) or CRH.

Cushing's disease refers to one specific cause of the syndrome, a tumor (adenoma) in the pituitary gland that produces large amounts of ACTH, which in turn elevates cortisol. It is the most common cause of Cushing's syndrome, responsible for 70% of cases excluding glucocorticoid related cases.

This pathology was described by Harvey Cushing in 1932. The syndrome is also called Itsenko-Cushing syndrome,hyperadrenocorticism or hypercorticism)

Cushing's syndrome is not confined to humans and is also a relatively common condition in domestic dogs and horses.

Pathophysiology

Excess levels of either exogenously administered glucocorticoids or endogenous overproduction of cortisol causes Cushing syndrome. Endogenous glucocorticoid overproduction or hypercortisolism that is independent of ACTH is usually due to a primary adrenocortical neoplasm (usually an adenoma but rarely a carcinoma). Bilateral micronodular hyperplasia and macronodular hyperplasia are rare causes of Cushing syndrome.

ACTH-secreting neoplasms cause ACTH-dependent Cushing syndrome. They usually are due to an anterior pituitary tumor, that is, classic Cushing disease (80%). Nonpituitary ectopic sources of ACTH, such as an oat cell carcinoma, small-cell lung carcinoma, or carcinoid tumor, cause the balance of ACTH-dependent disease. Ectopic corticotropin-releasing hormone (CRH) secretion leading to increased ACTH secretion comprise a very rare group of cases of Cushing syndrome.

Causes

Cushing's syndrome results from excess levels of the hormone cortisol in your body. Your endocrine system consists of glands that produce hormones, such as cortisol, that regulate processes throughout your body. These glands include the adrenal glands, pituitary gland, thyroid gland, parathyroid glands, pancreas, ovaries (in females) and testicles (in men).

Your adrenal glands produce a number of hormones, including cortisol. Cortisol plays a variety of roles in your body. For example, cortisol helps regulate your blood pressure and keeps your cardiovascular system functioning normally. It also helps your body respond to stress and regulates the way you convert (metabolize) proteins, carbohydrates and fats in your diet into usable energy. However, when the level of cortisol is too high in your body, you may develop Cushing's syndrome.

The role of corticosteroids Cushing's syndrome can develop from a cause that originates outside of your body (exogenous Cushing's syndrome). Taking corticosteroid medications in high doses over an extended period of time may result in Cushing's syndrome. These medications, such as prednisone, have the same effects as does the cortisol produced by your body.

Your doctor may prescribe corticosteroids to treat inflammatory diseases, such as rheumatoid arthritis, lupus and asthma, or to prevent your body from rejecting a transplanted organ. Because the doses required to treat these conditions are often higher than the amount of cortisol your body normally needs each day, the effects of excess cortisol can occur.

People can also develop Cushing's from injectable corticosteroids — for example, repeated injections for joint pain, bursitis and back pain. While certain inhaled steroid medicines (taken for asthma) and steroid skin creams (for skin disorders such as eczema) are in the same general category of drugs, they're generally not involved in Cushing's syndrome unless taken in high doses.

Your body's own overproduction The condition may also be due to your body's own overproduction of cortisol (endogenous Cushing's syndrome). This may occur from excess production by one or both adrenal glands, or overproduction of the adrenocorticotropic hormone (ACTH), which normally regulates cortisol production. In these cases, Cushing's syndrome may be related to:

A pituitary gland tumor. A noncancerous (benign) tumor of the pituitary gland, located at the base of the brain, secretes an excess amount of ACTH, which in turn stimulates the adrenal glands to make more cortisol. When this form of the syndrome develops, it's called Cushing's disease. It occurs much more often in women and is the most common form of endogenous Cushing's syndrome.

An ectopic ACTH-secreting tumor. Rarely, when a tumor develops in an organ that normally does not produce ACTH, the tumor will begin to secrete this hormone in excess, resulting in Cushing's syndrome. These tumors, which can be noncancerous (benign) or cancerous (malignant), are usually found in a lung, pancreas, thyroid or thymus gland.

A primary adrenal gland disease. In some people, the cause of Cushing's syndrome is excess cortisol secretion that doesn't depend on stimulation from ACTH and is associated with disorders of the adrenal glands. The most common of these disorders is a noncancerous tumor of the adrenal cortex, called an adrenal adenoma. Cancerous tumors of the adrenal cortex are rare, but they can cause Cushing's syndrome as well. Malignant tumors of the adrenal glands (adrenocortical carcinoma) are rare, and sometimes produce excess cortisol. Occasionally, benign, nodular enlargement of both adrenal glands can result in Cushing's syndrome.

Familial Cushing's syndrome. Rarely, people inherit a tendency to develop tumors on one or more of their endocrine glands, affecting cortisol levels and causing Cushing's syndrome.

Symptoms

The signs and symptoms of Cushing's syndrome vary.

Common signs and symptoms involve progressive obesity and skin changes, such as:

Weight gain and fatty tissue deposits, particularly around the midsection and upper back, in the face (moon face) and between the shoulders (buffalo hump)

Pink or purple stretch marks (striae) on the skin of the abdomen, thighs, breasts and arms

Thinning, fragile skin that bruises easily

Slow healing of cuts, insect bites and infections

Acne

Women with Cushing's syndrome may experience:

Thicker or more visible body and facial hair (hirsutism)

Irregular or absent menstrual periods

Men with Cushing's syndrome may experience:

Decreased libido

Decreased fertility

Erectile dysfunction

Other signs and symptoms include:

Fatigue

Muscle weakness

Depression, anxiety and irritability

Loss of emotional control

Cognitive difficulties

New or worsened high blood pressure

Glucose intolerance that may lead to diabetes

Headache

Bone loss, leading to fractures over time

Exams and Tests

Cushing's syndrome can be difficult to diagnose, particularly endogenous Cushing's, because other conditions share the same signs and symptoms.

Your doctor will conduct a physical exam, looking for signs of Cushing's syndrome. He or she may suspect Cushing's syndrome if you have signs such as rounding of the face (moon face), a pad of fatty tissue between the shoulders and neck (buffalo hump), and thin skin with bruises and stretch marks.

If you've been taking a corticosteroid medication for a long time, your doctor may suspect that you've developed Cushing's syndrome as a result of this medication. If you haven't been using a corticosteroid medication, these diagnostic tests may help pinpoint the cause:

Urine and blood tests. These tests measure hormone levels in your urine and blood and show whether your body is producing excessive cortisol. For the urine test, you may be asked to collect your urine over a 24-hour period. Both the urine and blood samples will be sent to a laboratory to be analyzed for cortisol levels.

Your doctor might also recommend other specialized tests that evaluate the blood and urine to help determine if Cushing's syndrome is present and to help identify the underlying source of any excess production. These tests often involve measuring cortisol levels before and after stimulation or suppression with other hormone medications.

Saliva test. Cortisol levels normally rise and fall throughout the day. In people without Cushing's syndrome, levels of cortisol drop significantly in the evening. By analyzing cortisol levels from a small sample of saliva collected late at night, doctors can see if cortisol levels are too high, suggesting a diagnosis of Cushing's.

Imaging tests. Computerized tomography (CT) scans or magnetic resonance imaging (MRI) scans can provide images of your pituitary and adrenal glands to detect abnormalities, such as tumors.

As these tests help your doctor diagnose Cushing's syndrome, they may also rule out medical conditions with similar signs and symptoms. For example, polycystic ovary syndrome — a hormone disorder in women with enlarged ovaries — shares some of the same signs and symptoms as Cushing's has, such as excessive hair growth and irregular menstrual periods. Depression, eating disorders and alcoholism also can partially mimic Cushing's syndrome.

Treatment

Treatments for Cushing's syndrome are designed to lower the high level of cortisol in your body. The best treatment for you depends on the cause of the syndrome. Treatment options include:

Reducing corticosteroid use. If the cause of Cushing's syndrome is long-term use of corticosteroid medications, your doctor may be able to keep your Cushing's signs and symptoms under control by reducing the dosage of the drug over a period of time, while still adequately managing your asthma, arthritis or other condition. For many of these medical problems, your doctor can prescribe noncorticosteroid drugs, which will allow him or her to reduce the dosage or eliminate the use of corticosteroids altogether.

Don't reduce the dose of corticosteroid drugs or stop taking them on your own. Do so only under your doctor's supervision. Abruptly discontinuing these medications could lead to deficient cortisol levels. Slowly tapering off corticosteroid drugs allows your body to resume normal cortisol production.

Surgery. If the cause of Cushing's syndrome is a tumor, your doctor may recommend complete surgical removal. Pituitary tumors are typically removed by a neurosurgeon, who may perform the procedure through your nose. If a tumor is present in the adrenal glands, lungs or pancreas, the surgeon can remove it through a standard operation or in some cases by using minimally invasive surgical techniques, with smaller incisions.

After the operation, you'll need to take cortisol replacement medications to provide your body with the correct amount of cortisol. In most cases, you'll eventually experience a return of normal adrenal hormone production, and your doctor can taper off the replacement drugs. However, this process can take up to a year or longer. In some instances, people with Cushing's syndrome never experience a resumption of normal adrenal function; they then need lifelong replacement therapy.

Radiation therapy. If the surgeon can't totally remove a pituitary tumor, he or she will usually prescribe radiation therapy to be used in conjunction with the operation. Additionally, radiation may be used for people who aren't suitable candidates for surgery. Radiation can be given in small doses over a six-week period, or by a technique called stereotactic radiosurgery or gamma-knife radiation. In the latter procedure, administered as a single treatment, a large dose of radiation is delivered to the tumor, and the radiation exposure to surrounding tissues is minimized.

Medications. Medications can be used to control cortisol production when surgery and radiation don't work. Medications may also be used before surgery in people who have become very sick with Cushing's syndrome. Doctors recommend drug therapy before surgery to improve signs and symptoms and minimize surgical risk. Medications to control excessive production of cortisol include ketoconazole (Nizoral), mitotane (Lysodren) and metyrapone (Metopirone).

In some cases, the tumor or its treatment will cause other hormones produced by the pituitary or adrenal gland to become deficient and your doctor will recommend hormone replacement medications.

If none of these treatment options is effective, your doctor may recommend surgical removal of your adrenal glands (bilateral adrenalectomy). This procedure will cure excess production of cortisol. However, your ACTH levels will remain high, possibly causing excess pigmentation of your skin.