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Gallstone From Wikipedia, the free encyclopedia

Jump to: navigation, search Gallstone Classification and external resources

gallstones

ICD-10

K80.

ICD-9

574

OMIM

600803

DiseasesDB

2533

MedlinePlus

000273

eMedicine

emerg/97

MeSH

D042882

Gall bladder opened to show numerous gallstones. Their brownish to greenish color suggest they are cholesterol calculi.

In medicine, gallstones (choleliths) are crystalline bodies formed within the body by accretion or concretion of normal or abnormal bile component. Gallstones can occur anywhere within the biliary tree, including the gallbladder and the common bile duct. Obstruction of the common bile duct is choledocholithiasis; obstruction of the biliary tree can cause jaundice; obstruction of the outlet of the pancreatic exocrine system can cause pancreatitis. Cholelithiasis is the presence of stones in the gallbladder—chole- means "bile", lithia means "stone", and -sis means "process".

Contents [hide]

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1 Characteristics o 1.1 Size o 1.2 Content  1.2.1 Mixed stones  1.2.2 Pseudolithiasis 2 Causes 3 Symptoms 4 Treatment o 4.1 Medical options o 4.2 Surgical options o 4.3 Alternative medicine 5 Value 6 References

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7 External links

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[edit] Characteristics [edit] Size A gallstone's size varies and may be as small as a sand grain or as large as a golf ball. The gallbladder may develop a single, often large stone or many smaller ones. They may occur in any part of the biliary system.

[edit] Content

Gallstones Gallstones have different appearance, depending on their contents. On the basis of their contents, gallstones can be subdivided into the two following types: •

Cholesterol stones are usually green, but are sometimes white or yellow in color. They are made primarily of cholesterol.

•

Pigment stones are small, dark stones made of bilirubin and calcium salts that are found in bile. They account for 20 percent of gallstones. Risk factors for pigment stones include hemolytic anemia, cirrhosis, biliary tract infections, and hereditary blood cell disorders, such as sickle cell anemia and spherocytosis.

[edit] Mixed stones Mixed stones account for the majority of stones. Most of these are a mixture of cholesterol and calcium salts. Because of their calcium content, they can often be visualized radiographically. [edit] Pseudolithiasis A.k.a., "Fake stone" Sludge-like gallbladder secretions that act like a stone.

[edit] Causes Researchers believe that gallstones may be caused by a combination of factors, including inherited body chemistry, body weight, gallbladder motility (movement), and perhaps diet. Additionally, people with erythropoietic protoporphyria (EPP) are at increased risk to develop gallstones.[1] Cholesterol gallstones develop when bile contains too much cholesterol and not enough bile salts. Besides a high concentration of cholesterol, two other factors seem to be important in causing gallstones. The first is how often and how well the gallbladder contracts; incomplete and infrequent emptying of the gallbladder may cause the bile to become overconcentrated and contribute to gallstone formation. The second factor is the presence of proteins in the liver and bile that either promote or inhibit cholesterol crystallization into gallstones.

In addition, increased levels of the hormone estrogen as a result of pregnancy, hormone therapy, or the use of combined (estrogen-containing) forms of hormonal contraception, may increase cholesterol levels in bile and also decrease gallbladder movement, resulting in gallstone formation. No clear relationship has been proven between diet and gallstone formation. However, low-fibre, high-cholesterol diets, and diets high in starchy foods have been suggested as contributing to gallstone formation. Other nutritional factors that may increase risk of gallstones include rapid weight loss, constipation, eating fewer meals per day, eating less fish, and low intakes of the nutrients folate, magnesium, calcium, and vitamin C.[2] On the other hand, wine and whole grain bread may decrease the risk of gallstones.[3] The common mnemonic for gallstone risk factors refer to the "four F's": fat (i.e., overweight), forty (an age near or above 40), female, and fertile (pre-menopausal);[4] a fifth F, fair is sometimes added to indicate that the condition is more prevalent in Caucasians. The absence of these risk factors does not, however, preclude the formation of gallstones.

[edit] Symptoms Gallstones usually remain asymptomatic initially.[5] They start developing symptoms once the stones reach a certain size (>8mm).[6] A main symptom of gallstones is commonly referred to as a gallstone "attack", also known as biliary colic, in which a person will experience intense pain in the upper abdominal region that steadily increases for approximately thirty minutes to several hours. A patient may also encounter pain in the back, ordinarily between the shoulder blades, or pain under the right shoulder. In some cases, the pain develops in the lower region of the abdomen, nearer to the pelvis, but this is less common.[citation needed] Nausea and vomiting may occur. These attacks are sharp and intensely painful, similar to that of a kidney stone attack. One way to alleviate the abdominal pain is to drink a full glass of water at the start of an attack to regulate the bile in the gallbladder, but this does not work in all cases.[citation needed] Another way is to take magnesium followed by a bitter liquid such as coffee or swedish bitters an hour later.[citation needed] Bitter flavors stimulate bile flow.[citation needed] A study has found lower rates of gallstones in coffee drinkers.[7] Often, these attacks occur after a particularly fatty meal and almost always happen at night. Other symptoms include abdominal bloating, intolerance of fatty foods, belching, gas, and indigestion. If the above symptoms coincide with chills, lowgrade fever, yellowing of the skin or eyes, and/or clay-colored stool, a doctor should be consulted immediately.[8] Some people who have gallstones are asymptomatic and do not feel any pain or discomfort. These gallstones are called "silent stones" and do not affect the gallbladder or other internal organs. They do not need treatment.[8]

[edit] Treatment [edit] Medical options Cholesterol gallstones can sometimes be dissolved by oral ursodeoxycholic acid, but it may be required that the patient takes this medication for up to two years[9]. Gallstones may recur however, once the drug is stopped. Obstruction of the common bile duct with gallstones can sometimes be relieved by endoscopic retrograde sphincterotomy (ERS) following endoscopic retrograde cholangiopancreatography (ERCP). Gallstones can be broken up using a procedure called lithotripsy (Extracorporeal Shock Wave Lithotripsy)[9], which is a method of concentrating ultrasonic shock waves onto the stones to break them into tiny pieces. They are then passed safely in the feces. However, this form of treatment is only suitable when there are a small number of gallstones.

[edit] Surgical options Cholecystectomy (gallbladder removal) has a 99% chance of eliminating the recurrence of cholelithiasis. Only symptomatic patients must be indicated to surgery. The lack of a gall bladder does not seem to have any negative consequences in many people. However, there is a significant proportion of the population, between 5-40%, who develop a condition called postcholecystectomy syndrome.[10]Symptoms include gastrointestinal distress and persistent pain in the upper right abdomen. As many as twenty percent of patients develop chronic diarrhea.[11] There are two surgery options: open procedure and laparoscopic: see the cholecystectomy article for more details. •

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Open cholecystectomy procedure: This involves a large incision into the abdomen (laparotomy) below the right lower ribs. A week of hospitalization, normal diet a week after release and normal activity a month after release. Laparoscopic cholecystectomy: Three to four small puncture holes for camera and instruments (available since the 1980s). Typically same-day release or one night hospital stay, followed by a week of home rest and pain medication. Can resume normal diet and light activity a week after release. (Decreased energy level and minor residual pain for a month or two.) Studies have shown that this procedure is as effective as the more invasive open cholecystectomy, provided the stones are accurately located by cholangiogram prior to the procedure so that they can all be removed. The procedure also has the benefit of reducing operative complications such as bowel perforation and vascular injury.

[edit] Alternative medicine A regimen called a "gallbladder flush" or "liver flush" is a popular remedy in alternative medicine.[12] In this treatment, often self-administered, the patient drinks four glasses of pure apple juice (not cider) and eats five apples (or applesauce) per day for five days,

then fasts briefly, takes magnesium, and then drinks large quantities of lemon juice mixed with olive oil before bed. The next morning, they painlessly pass a number of green and brown pebbles purported to be stones flushed from the biliary system. A New Zealand hospital analyzed stones from a typical gallbladder flush and found them to be composed of fatty acids similar to those in olive oil, with no detectable cholesterol or bile salts,[13] demonstrating that they are little more than hardened olive oil. Despite the gallbladder flush, the patient still required surgical removal of multiple true gallstones. The note concluded: "The gallbladder flush may not be entirely worthless, however; there is one case report in which treatment with olive oil and lemon juice resulted in the passage of numerous gallstones, as demonstrated by ultrasound examination."[14] In the case mentioned, ultrasound confirmed multiple gallstones, but after waiting months for a surgical option, the patient underwent a treatment with olive oil and lemon juice resulting in the passage of four 2.5–cm by 1.25–cm stones and twenty pea-sized stones. Two years later symptoms returned, and ultrasound showed a single large gallstone; the patient chose to have this removed surgically.[14] Other patients have noticed that symptoms can be reduced by drinking several glasses of water when experiencing gallstone pain. This will obviously not eliminate the gallstones, but can temporarily reduce the pain.[citation needed]

[edit] Value Gallstones are a valuable by-product of meat processing, fetching up to US$32–per–gram in their use as a purported antipyretic and antidote in the herbal medicine of some cultures, particularly in China. The finest gallstones tend to be sourced from old dairy cows, which are called Niu-Huang (yellow thing of oxen) in Chinese. Those obtained from dogs, called Gou-Bao (treasure of dogs) in Chinese, are also used today. Much as in the manner of diamond mines, slaughterhouses carefully scrutinize offal department workers for gallstone theft Pancreatitis is the inflammation of the pancreas. See also acute pancreatitis and chronic pancreatitis for more details.

Contents [hide] •

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1 Classification o 1.1 Acute pancreatitis o 1.2 Chronic pancreatitis 2 Causes o 2.1 Porphyrias

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2.2 Medications 2.3 Genetics 3 Symptoms and signs 4 Diagnosis o 4.1 Laboratory tests o 4.2 Imaging 5 Prognosis o 5.1 APACHE II o 5.2 Ranson criteria 6 Interpretation o 6.1 Glasgow criteria 7 Complications o 7.1 Late complications 8 Treatment

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9 References

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[edit] Classification There are different forms of pancreatitis, which are different in causes and symptoms, and require different treatment:

[edit] Acute pancreatitis Main article: Acute pancreatitis Acute pancreatitis is an acute episode of pancreatitis.

[edit] Chronic pancreatitis Main article: Chronic pancreatitis Chronic pancreatitis is the "inflammation of the pancreas that is characterized by recurring or persistent abdominal pain with or without steatorrhea or diabetes mellitus"[1]

[edit] Causes The most common cause of acute pancreatitis is gallstones. Excessive alcohol use is often cited as the second most common cause of acute pancreatitis. Less common causes include hypertriglyceridemia (but not hypercholesterolemia) and only when triglyceride values exceed 1500 mg/dl (16 mmol/L), hypercalcemia, viral infection (e.g. mumps), trauma (to the abdomen or elsewhere in the body) including post-ERCP (i.e. Endoscopic Retrograde Cholangiopancreatography), vasculitis (i.e. inflammation of the small blood vessels within the pancreas), and autoimmune pancreatitis. Pregnancy can also cause pancreatitis, but in some cases the development of pancreatitis is probably just a

reflection of the hypertriglyceridemia which often occurs in pregnant women. Pancreas divisum, a common congenital malformation of the pancreas may underlie some cases of recurrent pancreatitis. The more mundane, but far more common causes of pancreatitis, as mentioned above, must always be considered first. However, the known porphyrinogenicity of many drugs, hormones, alcohol, chemicals and the association of porphyrias with autoimmune disorders and gallstones do not exclude the diagnosis of heme disorders when these explanations are used. A primary medical disorder, including an underlying undetected inborn error in metabolism, supersedes a secondary medical complication or explanation. Autoimmune disorders, lipid disorders, gallstones, drug reactions and pancreatitis itself are not primary medical disorders. It is worth noting that pancreatic cancer is seldom the cause of pancreatitis.[citation needed] People with diabetes should promptly seek medical care if they experience unexplained severe abdominal pain with or without nausea and vomiting. [2] A useful mnemonic for remembering the causes of acute pancreatitis is; 'I GET SMASHED', that is: • • • • • • • • • • •

Idiopathic Gallstones Ethanol Trauma Steroids Mumps Autoimmune causes Scorpion venom Hyperlipidaemias ERCP Drugs (Such as Azathioprine)

[edit] Porphyrias Acute hepatic porphyrias, including acute intermittent porphyria, hereditary coproporphyria and variegate porphyria, are genetic disorders that can be linked to both acute and chronic pancreatitis. Acute pancreatitis has also occurred with erythropoietic protoporphyria. Conditions that can lead to gut dysmotility predispose patients to pancreatitis. This includes the inherited neurovisceral porphyrias and related metabolic disorders. Alcohol, hormones and many drugs including statins are known porphyrinogenic agents. Physicians should be on alert concerning underlying porphyrias in patients presenting

with pancreatitis and should investigate and eliminate any drugs that may be activating the disorders. Still, notwithstanding their potential role in pancreatitis, the porphyrias (as a group or individually) are considered to be rare disorders. However, since there are no systematic studies to determine the actual incidence of latent dominantly-inherited porphyrias in the world population, there is DNA or enzyme evidence of high rates of latency of classic textbook symptoms in families where porphyrias have been detected and the technology is not developed to detect all latent porphyrias, the diagnosis of underlying inborn errors of metabolism impacting heme should not be routinely eliminated in pancreatitis.

[edit] Medications Many medications have been reported to cause pancreatitis. Some of the more common ones include the AIDS drugs DDI and pentamidine, diuretics such as furosemide and hydrochlorothiazide, the chemotherapeutic agents L-asparaginase and azathioprine, and estrogen. Just as is the case with pregnancy-associated pancreatitis, estrogen may lead to the disorder because of its effect of raising blood triglyceride levels.

[edit] Genetics Hereditary pancreatitis may be due to a genetic abnormality that renders trypsinogen active within the pancreas, which in turn leads to digestion of the pancreas from the inside. Pancreatic diseases are notoriously complex disorders resulting from the interaction of multiple genetic, environmental and metabolic factors. Three candidates for genetic testing are currently under investigation: • • •

Trypsinogen mutations (Trypsin 1) Cystic Fibrosis Transmembrane Conductance Regulator Gene (CFTR) mutations SPINK1 which codes for PSTI - a specific trypsin inhibitor.[3]

[edit] Symptoms and signs Severe upper abdominal pain, with radiation through to the back, is the hallmark of pancreatitis. Nausea and vomiting (emesis) are prominent symptoms. Findings on the physical exam will vary according to the severity of the pancreatitis, and whether or not it is associated with significant internal bleeding. The blood pressure may be high (when pain is prominent) or low (if internal bleeding or dehydration has occurred). Typically, both the heart and respiratory rates are elevated. Abdominal tenderness is usually found but may be less severe than expected given the patient's degree of abdominal pain. Bowel sounds may be reduced as a reflection of the reflex bowel paralysis (i.e. ileus) that may accompany any abdominal catastrophe.

[edit] Diagnosis The diagnostic criteria for pancreatitis are "two of the following three features: 1) abdominal pain characteristic of acute pancreatitis, 2) serum amylase and/or lipase ≥3 times the upper limit of normal, and 3) characteristic findings of acute pancreatitis on CT scan."[4]

[edit] Laboratory tests Most frequently, measurement is made of amylase and/or lipase, and often one, or both, are elevated in cases of pancreatitis. Two practice guidelines state: It is usually not necessary to measure both serum amylase and lipase. Serum lipase may be preferable because it remains normal in some nonpancreatic conditions that increase serum amylase including macroamylasemia, parotitis, and some carcinomas. In general, serum lipase is thought to be more sensitive and specific than serum amylase in the diagnosis of acute pancreatitis".[4] Although amylase is widely available and provides acceptable accuracy of diagnosis, where lipase is available it is preferred for the diagnosis of acute pancreatitis (recommendation grade A)".[5] Most,[6][7] [8][9][10] but not all[11][12] individual studies support the superiority of the lipase. In one large study, there were no patients with pancreatitis who had an elevated amylase with a normal lipase.[6] Another study found that the amylase could add diagnostic value to the lipase, but only if the results of the two tests were combined with a discriminant function equation.[13] Conditions other than pancreatitis may lead to rises in these enzymes and, further, that those conditions may also cause pain that resembles that of pancreatitis (e.g. cholecystitis, perforated ulcer, bowel infarction (i.e. dead bowel as a result of poor blood supply), and even diabetic ketoacidosis.

[edit] Imaging Although ultrasound imaging and CT scanning of the abdomen can be used to confirm the diagnosis of pancreatitis, neither is usually necessary as a primary diagnostic modality[14] . In addition, CT contrast may exacerbate pancreatitis,[15] although this is disputed.[16] See acute pancreatitis.

[edit] Prognosis There are several scoring systems used to help predict the severity of an attack of pancreatitis. The Apache II has the advantage of being available at the time of admission

as opposed to 48 hours later for the Glasgow criteria and Ranson criteria. However, the Glasgow criteria and Ranson criteria are easier to use.

[edit] APACHE II Main article: APACHE II

[edit] Ranson criteria Main article: Ranson criteria At admission: 1. 2. 3. 4. 5.

age in years > 55 years white blood cell count > 16000 /mcL blood glucose > 11 mmol/L (>200 mg/dL) serum AST > 250 IU/L serum LDH > 350 IU/L

After 48 hours: 1. Haematocrit fall > 11.3444% 2. increase in BUN by 1.8 or more mmol/L (5 or more mg/dL) after IV fluid hydration 3. hypocalcemia (serum calcium < 2.0 mmol/L (<8.0 mg/dL)) 4. hypoxemia (PO2 < 60 mmHg) 5. Base deficit > 4 Meq/L 6. Estimated fluid sequestration > 6 L The criteria for point assignment is that a certain breakpoint be met at anytime during that 48 hour period, so that in some situations it can be calculated shortly after admission. It is applicable to both biliary and alcoholic pancreatitis.

[edit] Interpretation • •

If the score ≥ 3, severe pancreatitis likely. If the score < 3, severe pancreatitis is unlikely

• • • •

Score 0 to 2: 2% mortality Score 3 to 4: 15% mortality Score 5 to 6: 40% mortality Score 7 to 8: 100% mortality

Or

[edit] Glasgow criteria Glasgow's criteria[17]: The original system used 9 data elements. This was subsequently modified to 8 data elements, with removal of assessment for transaminase levels (either AST (SGOT) or ALT (SGPT) greater than 100 U/L). On Admission 1. 2. 3. 4. 5.

Age >55 yrs WBC Count >15 x109/L Blood Glucose >10 mmol/L (No Diabetic History) Serum Urea >16 mmol/L ( No response to IV fluids) Arterial Oxygen Saturation <60 mmHg

Within 48 hours 1. 2. 3. 4.

Serum Calcium <2 mmol/L Serum Albumin <32 g/L LDH >600 units/L AST/ALT >200 units/L

[edit] Complications Acute (early) complications of pancreatitis include • • • •

•

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shock, hypocalcemia (low blood calcium), high blood glucose, dehydration, and kidney failure (resulting from inadequate blood volume which, in turn, may result from a combination of fluid loss from vomiting, internal bleeding, or oozing of fluid from the circulation into the abdominal cavity in response to the pancreas inflammation, a phenomenon known as Third Spacing). Respiratory complications are frequent and are major contributors to the mortality of pancreatitis. Some degree of pleural effusion is almost ubiquitous in pancreatitis. Some or all of the lungs may collapse (atelectasis) as a result of the shallow breathing which occurs because of the abdominal pain. Pneumonitis may occur as a result of pancreatic enzymes directly damaging the lung, or simply as a final common pathway response to any major insult to the body (i.e. ARDS or Acute Respiratory Distress Syndrome). Likewise, SIRS (Systemic inflammatory response syndrome) may ensue. Infection of the inflamed pancreatic bed can occur at any time during the course of the disease. In fact, in cases of severe hemorrhagic pancreatitis, antibiotics should be given prophylactically.

[edit] Late complications Late complications include recurrent pancreatitis and the development of pancreatic pseudocysts. A pancreatic pseudocyst is essentially a collection of pancreatic secretions which has been walled off by scar and inflammatory tissue. Pseudocysts may cause pain, may become infected, may rupture and hemorrhage, may press on and block structures such as the bile duct, thereby leading to jaundice, and may even migrate around the abdomen.

[edit] Treatment The treatment of pancreatitis will, of course, depend on the severity of the pancreatitis itself. Still, general principles apply and include: 1. Provision of pain relief. In the past this was done preferentially with meperidine (Demerol), but it is now not thought to be superior to any narcotic analgesic. Indeed, given meperidine's generally poor analgesic charactersitics and its high potential for toxicity, it should not be used for the treatment of the pain of pancreatitis. The preferred analgesic is morphine for acute pancreatitis. 2. Provision of adequate replacement fluids and salts (intravenously). 3. Limitation of oral intake (with dietary fat restriction the most important point). NG tube feeding is the preferred method to avoid pancreatic stimulation and possible infection complications caused by bowel flora. 4. Monitoring and assessment for, and treatment of, the various complications listed above. When necrotizing pancreatitis ensues and the patient shows signs of infection, it is imperative to start antibiotics such as Imipenem due to the high penetration of the drug in the pancreas. Floroquinolone + metronidazole is another treatment option.

Cirrhosis From Wikipedia, the free encyclopedia

Jump to: navigation, search Cirrhosis Classification and external resources

Cirrhosis leading to hepatocellular carcinoma (autopsy specimen).

ICD-10

K70.3, K71.7, K74.

ICD-9

571

DiseasesDB 2729 eMedicine

med/3183 radio/175

MeSH

D008103

Liver cirrhosis as seen on an axial CT of the abdomen. Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrous scar tissue as well as regenerative nodules (lumps that occur as a result of a process in which damaged tissue is regenerated),[1][2][3] leading to progressive loss of liver function. Cirrhosis is most commonly caused by alcoholism, hepatitis B and C and fatty liver disease but has many other possible causes. Some cases are cryptogenic, i.e, of unknown cause, but most of these are probably due to previously unrecognised fatty liver disease.

Ascites (fluid retention in the abdominal cavity) is the most common complication of cirrhosis and is associated with a poor quality of life, increased risk of infection, and a poor long-term outcome. Other potentially life-threatening complications are hepatic encephalopathy (confusion and coma) and bleeding from esophageal varices. Cirrhosis is generally irreversible once it occurs, and treatment generally focuses on preventing progression and complications. In advanced stages of cirrhosis the only option is a liver transplant. The word "cirrhosis" derives from Greek kirrhos, meaning "tawny" (the orange-yellow colour of the diseased liver). While the clinical entity was known before, it was René Laennec who gave it the name "cirrhosis" in his 1819 work in which he also describes the stethoscope.[4]

Contents [hide]

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1 Signs and symptoms 2 Complications 3 Causes 4 Diagnosis o 4.1 Lab findings o 4.2 Imaging o 4.3 Endoscopy o 4.4 Pathology 5 Grading 6 Pathophysiology 7 Treatment o 7.1 Treating underlying causes o 7.2 Preventing further liver damage o 7.3 Preventing complications  7.3.1 Ascites  7.3.2 Esophageal variceal bleeding  7.3.3 Hepatic encephalopathy  7.3.4 Hepatorenal syndrome  7.3.5 Spontaneous bacterial peritonitis o 7.4 Transplantation o 7.5 Decompensated cirrhosis 8 Epidemiology 9 References

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10 External links

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[edit] Signs and symptoms

Some of the following signs and symptoms may occur in the presence of cirrhosis or as a result of the complications of cirrhosis. Many are nonspecific and may occur in other diseases and do not necessarily point to cirrhosis. Likewise, the absence of any does not rule out the possibility of cirrhosis. •

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Spider angiomata or spider nevi. Vascular lesions consisting of a central arteriole surrounded by many smaller vessels due to an increase in estradiol. These occur in about 1/3 of cases.[5] Palmar erythema. Exaggerations of normal speckled mottling of the palm, due to altered sex hormone metabolism. Nail changes. o Muehrcke's nails - paired horizontal bands separated by normal color due to hypoalbuminemia (low production of albumin). o Terry's nails - proximal two thirds of the nail plate appears white with distal one-third red, also due to hypoalbuminemia o Clubbing - angle between the nail plate and proximal nail fold > 180 degrees Hypertrophic osteoarthropathy. Chronic proliferative periostitis of the long bones that can cause considerable pain. Dupuytren's contracture. Thickening and shortening of palmar fascia that leads to flexion deformities of the fingers. Thought to be due to fibroblastic proliferation and disorderly collagen deposition. It is relatively common (33% of patients). Gynecomastia. Benign proliferation of glandular tissue of male breasts presenting with a rubbery or firm mass extending concentrically from the nipples. This is due to increased estradiol and can occur in up to 66% of patients. Hypogonadism. Manifested as impotence, infertility, loss of sexual drive, and testicular atrophy due to primary gonadal injury or suppression of hypothalamic or pituitary function. Liver size. Can be enlarged, normal, or shrunken. Splenomegaly (increase in size of the spleen). Due to congestion of the red pulp as a result of portal hypertension. Ascites. Accumulation of fluid in the peritoneal cavity giving rise to flank dullness (needs about 1500 mL to detect flank dullness). It may be associated with hydrocele and penile flomation (swelling of the penile shaft) in men. Caput medusa. In portal hypertension, the umbilical vein may open. Blood from the portal venous system may be shunted through the periumbilical veins into the umbilical vein and ultimately to the abdominal wall veins, manifesting as caput medusa. Cruveilhier-Baumgarten murmur. Venous hum heard in epigastric region (on examination by stethoscope) due to collateral connections between portal system and the remnant of the umbilical vein in portal hypertension. Fetor hepaticus. Musty odor in breath due to increased dimethyl sulfide. Jaundice. Yellow discoloring of the skin, eye, and mucus membranes due to increased bilirubin (at least 2-3 mg/dL or 30 mmol/L). Urine may also appear dark.

• •

Asterixis. Bilateral asynchronous flapping of outstretched, dorsiflexed hands seen in patients with hepatic encephalopathy. Other. Weakness, fatigue, anorexia, weight loss.

[edit] Complications As the disease progresses, complications may develop. In some people, these may be the first signs of the disease. • • • •

• • •

•

Bruising and bleeding due to decreased production of coagulation factors. Jaundice due to decreased processing of bilirubin. Itching (pruritus) due to bile products deposited in the skin. Hepatic encephalopathy - the liver does not clear ammonia and related nitrogenous substances from the blood, which are carried to the brain, affecting cerebral functioning: neglect of personal appearance, unresponsiveness, forgetfulness, trouble concentrating, or changes in sleep habits. Sensitivity to medication due to decreased metabolism of the active compounds. Hepatocellular carcinoma is primary liver cancer, a frequent complication of cirrhosis. It has a high mortality rate. Portal hypertension - blood normally carried from the intestines and spleen through the hepatic portal vein flows more slowly and the pressure increases; this leads to the following complications: o Ascites - fluid leaks through the vasculature into the abdominal cavity. o Esophageal varices - collateral portal blood flow through vessels in the stomach and esophagus. These blood vessels may become enlarged and are more likely to burst. Problems in other organs. o Cirrhosis can cause immune system dysfunction, leading to infection. Signs and symptoms of infection may be aspecific are more difficult to recognize (e.g. worsening encephalopathy but no fever). o Fluid in the abdomen (ascites) may become infected with bacteria normally present in the intestines (spontaneous bacterial peritonitis). o Hepatorenal syndrome - insufficient blood supply to the kidneys, causing acute renal failure. This complication has a very high mortality (over 50%). o Hepatopulmonary syndrome - blood bypassing the normal lung circulation (shunting), leading to cyanosis and dyspnea (shortness of breath), characteristically worse on sitting up.[6] o Portopulmonary hypertension - increased blood pressure over the lungs as a consequence of portal hypertension.[6]

[edit] Causes

Cirrhosis has many possible causes; sometimes more than one cause is present in the same patient. In the Western World, chronic alcoholism and hepatitis C are the most common causes. •

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Alcoholic liver disease (ALD). Alcoholic cirrhosis develops in 15% of individuals who drink heavily for more than a decade[citation needed]. There is great variability in the amount of alcohol needed to cause cirrhosis (as little as 3-4 drinks a day in some men and 2-3 in some women[citation needed]). Alcohol seems to injure the liver by blocking the normal metabolism of protein, fats, and carbohydrates. Patients may also have concurrent alcoholic hepatitis with fever, hepatomegaly, jaundice, and anorexia. AST and ALT are both elevated but less than 300 IU/L with a AST:ALT ratio > 2.0, a value rarely seen in other liver diseases. Liver biopsy may show hepatocyte necrosis, Mallory bodies, neutrophilic infiltration with perivenular inflammation. Chronic hepatitis C. Infection with this virus causes inflammation of and low grade damage to the liver that over several decades can lead to cirrhosis. Can be diagnosed with serologic assays that detect hepatitis C antibody or viral RNA. The enzyme immunoassay, EIA-2, is the most commonly used screening test in the US. Chronic hepatitis B. The hepatitis B virus is probably the most common cause of cirrhosis worldwide, especially South-East Asia, but it is less common in the United States and the Western world. Hepatitis B causes liver inflammation and injury that over several decades can lead to cirrhosis. Hepatitis D is dependent on the presence of hepatitis B, but accelerates cirrhosis in co-infection. Chronic hepatitis B can be diagnosed with detection of HBsAG > 6 months after initial infection. HBeAG and HBV DNA are determined to assess whether patient will need antiviral therapy. Non-alcoholic steatohepatitis (NASH). In NASH, fat builds up in the liver and eventually causes scar tissue. This type of hepatitis appears to be associated with diabetes, protein malnutrition, obesity, coronary artery disease, and treatment with corticosteroid medications. This disorder is similar to that of alcoholic liver disease but patient does not have an alcohol history. Biopsy is needed for diagnosis. Primary biliary cirrhosis. May be asymptomatic or complain of fatigue, pruritus, and non-jaundice skin hyperpigmentation with hepatomegaly. There is prominent alkaline phosphatase elevation as well as elevations in cholesterol and bilirubin. Gold standard diagnosis is antimitochondrial antibodies with liver biopsy as confirmation if showing florid bile duct lesions. It is more common in women. Primary sclerosing cholangitis. PSC is a progressive cholestatic disorder presenting with pruritus, steatorrhea, fat soluble vitamin deficiencies, and metabolic bone disease. There is a strong association with inflammatory bowel disease (IBD), especially ulcerative colitis. Diagnosis is best with contrast cholangiography showing diffuse, multifocal strictures and focal dilation of bile ducts, leading to a beaded appearance. Non-specific serum immunoglobulins may also be elevated.

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• • • • • •

Autoimmune hepatitis. This disease is caused by the immunologic damage to the liver causing inflammation and eventually scarring and cirrhosis. Findings include elevations in serum globulins, especially gamma globulins. Therapy with prednisone +/- azathioprine is beneficial. Cirrhosis due to autoimmune hepatitis still has 10-year survival of 90%+. There is no specific tool to diagnose autoimmune but it can be beneficial to initiate a trial of corticosteroids. Hereditary hemochromatosis. Usually presents with family history of cirrhosis, skin hyperpigmentation, diabetes mellitus, pseudogout, and/or cardiomyopathy, all due to signs of iron overload. Labs will show fasting transferrin saturation of > 60% and ferritin > 300 ng/mL. Genetic testing may be used to identify HFE mutations. If these are present, biopsy may not need to be performed. Treatment is with phlebotomy to lower total body iron levels. Wilson's disease. Autosomal recessive disorder characterized by low serum ceruloplasmin and increased hepatic copper content on liver biopsy. May also have Kayser-Fleischer rings in the cornea and altered mental status. Alpha 1-antitrypsin deficiency (AAT). Autosomal recessive disorder. Patients may also have COPD, especially if they have a history of tobacco smoking. Serum AAT levels are low. Recombinant AAT is used to prevent lung disease due to AAT deficiency. Cardiac cirrhosis. Due to chronic right sided heart failure which leads to liver congestion. Galactosemia Glycogen storage disease type IV Cystic fibrosis Drugs or toxins Certain parasitic infections (such as schistosomiasis)

[edit] Diagnosis The gold standard for diagnosis of cirrhosis is a liver biopsy, through a percutaneous, transjugular, laparoscopic, or fine-needle approach. Histologically cirrhosis can be classified as micronodular, macronodular, or mixed, but this classification has been abandoned since it is nonspecific to the etiology, it may change as the disease progresses, and serological markers are much more specific. However, a biopsy is not necessary if the clinical, laboratory, and radiologic data suggests cirrhosis. Furthermore, there is a small but significant risk to liver biopsy, and cirrhosis itself predisposes for complications due to liver biopsy.[7]

[edit] Lab findings The following findings are typical in cirrhosis: • •

Aminotransferases - AST and ALT are moderately elevated, with AST > ALT. However, normal aminotransferases do not preclude cirrhosis. Alkaline phosphatase - usually slightly elevated.

• • • • • • •

• •

GGT – correlates with AP levels. Typically much higher in chronic liver disease from alcohol. Bilirubin - may elevate as cirrhosis progresses. Albumin - levels fall as the synthetic function of the liver declines with worsening cirrhosis since albumin is exclusively synthesized in the liver Prothrombin time - increases since the liver synthesizes clotting factors. Globulins - increased due to shunting of bacterial antigens away from the liver to lymphoid tissue. Serum sodium - hyponatremia due to inability to excrete free water resulting from high levels of ADH and aldosterone. Thrombocytopenia - due to both congestive splenomegaly as well as decreased thrombopoietin from the liver. However, this rarely results in platelet count < 50,000/mL. Leukopenia and neutropenia - due to splenomegaly with splenic margination. Coagulation defects - the liver produces most of the coagulation factors and thus coagulopathy correlates with worsening liver disease.

Other laboratory studies performed in newly diagnosed cirrhosis may include: • • • • •

Serology for hepatitis viruses, autoantibodies (ANA, anti-smooth muscle, antimitochondria, anti-LKM) Ferritin and transferrin saturation (markers of iron overload), copper and ceruloplasmin (markers of copper overload) Immunoglobulin levels (IgG, IgM, IgA) - these are non-specific but may assist in distinguishing various causes Cholesterol and glucose Alpha 1-antitrypsin

[edit] Imaging Ultrasound is routinely used in the evaluation of cirrhosis, where it may show a small and nodular liver in advanced cirrhosis along with increased echogenicity with irregular appearing areas. Ultrasound may also screen for hepatocellular carcinoma, portal hypertension and Budd-Chiari syndrome (by assessing flow in the hepatic vein). A new type of device, the FibroScan (transient elastography), uses elastic waves to determine liver stiffness which theoretically can be converted into a liver score based on the METAVIR scale. The FibroScan produces an ultrasound image of the liver (from 2080mm) along with a pressure reading (in kPa.) The test is much faster than a biopsy (usually last 2.5-5 minutes) and is completely painless. It shows reasonable correlation with the severity of cirrhosis.[8] Other tests performed in particular circumstances include abdominal CT and liver/bile duct MRI (MRCP).

[edit] Endoscopy

Gastroscopy (endoscopic examination of the esophagus, stomach and duodenum) is performed in patients with established cirrhosis to exclude the possibility of esophageal varices. If these are found, prophylactic local therapy may be applied (sclerotherapy or banding) and beta blocker treatment may be commenced. Rarely diseases of the bile ducts, such as primary sclerosing cholangitis, can be causes of cirrhosis. Imaging of the bile ducts, such as ERCP or MRCP (MRI of biliary tract and pancreas) can show abnormalities in these patients, and may aid in the diagnosis.

[edit] Pathology Macroscopically, the liver may be initially enlarged, but with progression of the disease, it becomes smaller. Its surface is irregular, the consistency is firm and the color is often yellow (if associates steatosis). Depending on the size of the nodules there are three macroscopic types: micronodular, macronodular and mixed cirrhosis. In micronodular form (Laennec's cirrhosis or portal cirrhosis) regenerating nodules are under 3 mm. In macronodular cirrhosis (post-necrotic cirrhosis), the nodules are larger than 3 mm. The mixed cirrhosis consists in a variety of nodules with different sizes. Microscopically, cirrhosis is characterized by regeneration nodules, surrounded by fibrous septa. In these nodules, regenerating hepatocytes are disorderly disposed. Portal tracts, central veins and the radial pattern of hepatocytes are absent. Fibrous septa are important and may present inflammatory infiltrate (lymphocytes, macrophages) If it is a secondary biliary cirrhosis, biliary ducts are damaged, proliferated or distended - bile stasis. These dilated ducts contain inspissated bile which appear as bile casts or bile thrombi (brown-green, amorphous). Bile retention may be found also in the parenchyma, as the so called "bile lakes."[9]

[edit] Grading The severity of cirrhosis is commonly classified with the Child-Pugh score. This score uses bilirubin, albumin, INR, presence and severity of ascites and encephalopathy to classify patients in class A, B or C; class A has a favourable prognosis, while class C is at high risk of death. It was devised in 1964 by Child and Turcotte and modified in 1973 by Pugh et al.[10] More modern scores, used in the allocation of liver transplants but also in other contexts, are the Model for End-Stage Liver Disease (MELD) score and its pediatric counterpart, the Pediatric End-Stage Liver Disease (PELD) score. The hepatic venous pressure gradient, i.e. the difference in venous pressure between afferent and efferent blood to the liver, also determines severity of cirrhosis, although hard to measure. A value of 16 mm or more means a greatly increased risk of dying.[11]

[edit] Pathophysiology

The liver plays a vital role in synthesis of proteins (e.g. albumin, clotting factors and complement), detoxification and storage (e.g. vitamin A). In addition, it participates in the metabolism of lipids and carbohydrates. Cirrhosis is often preceded by hepatitis and fatty liver (steatosis), independent of the cause. If the cause is removed at this stage, the changes are still fully reversible. The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, blocking the portal flow of blood through the organ and disturbing normal function. Recent research shows the pivotal role of stellate cell, a cell type that normally stores vitamin A, in the development of cirrhosis. Damage to the hepatic parenchyma leads to activation of the stellate cell, which becomes contractile (called myofibroblast) and obstructs blood flow in the circulation. In addition, it secretes TGF-β1, which leads to a fibrotic response and proliferation of connective tissue. Furthermore, it disturbs the balance between matrix metalloproteinases and the naturally occurring inhibitors (TIMP 1 and 2), leading to matrix breakdown and replacement by connective tissue-secreted matrix.[12] The fibrous tissue bands (septa) separate hepatocyte nodules, which eventually replace the entire liver architecture, leading to decreased blood flow throughout. The spleen becomes congested, which leads to hypersplenism and increased sequestration of platelets. Portal hypertension is responsible for most severe complications of cirrhosis.

[edit] Treatment Generally, liver damage from cirrhosis cannot be reversed, but treatment could stop or delay further progression and reduce complications. A healthy diet is encouraged, as cirrhosis may be an energy-consuming process. Close follow-up is often necessary. Antibiotics will be prescribed for infections, and various medications can help with itching. Laxatives, such as lactulose, decrease risk of constipation; their role in preventing encephalopathy is limited.

[edit] Treating underlying causes Alcoholic cirrhosis caused by alcohol abuse is treated by abstaining from alcohol. Treatment for hepatitis-related cirrhosis involves medications used to treat the different types of hepatitis, such as interferon for viral hepatitis and corticosteroids for autoimmune hepatitis. Cirrhosis caused by Wilson's disease, in which copper builds up in organs, is treated with chelation therapy (e.g. penicillamine) to remove the copper.

[edit] Preventing further liver damage Regardless of underlying cause of cirrhosis, alcohol and acetaminophen, as well as other potentially damaging substances, are discouraged. Vaccination of susceptible patients should be considered for Hepatitis A and Hepatitis B.

[edit] Preventing complications [edit] Ascites Main article: Ascites Salt restriction is often necessary, as cirrhosis leads to accumulation of salt (sodium retention). Diuretics may be necessary to suppress ascites. [edit] Esophageal variceal bleeding Main article: Esophageal varices For portal hypertension, propranolol is a commonly used agent to lower blood pressure over the portal system. In severe complications from portal hypertension, transjugular intrahepatic portosystemic shunting is occasionally indicated to relieve pressure on the portal vein. As this can worsen encephalopathy, it is reserved for those at low risk of encephalopathy, and is generally regarded only as a bridge to liver transplantation or as a palliative measure. [edit] Hepatic encephalopathy Main article: Hepatic encephalopathy High-protein food increases the nitrogen balance, and would theoretically increase encephalopathy; in the past, this was therefore eliminated as much as possible from the diet. Recent studies show that this assumption was incorrect, and high-protein foods are even encouraged to maintain adequate nutrition. [edit] Hepatorenal syndrome Main article: Hepatorenal syndrome The hepatorenal syndrome is defined as a urine sodium less than 10 mmol/L and a serum creatinine > 1.5 mg/dl (or 24 hour creatinine clearance less than 40 ml/min) after a trial of volume expansion without diuretics.[13] [edit] Spontaneous bacterial peritonitis Main article: Spontaneous bacterial peritonitis Cirrhotic patients with ascites are at risk of spontaneous bacterial peritonitis.

[edit] Transplantation Main article: Liver transplantation

If complications cannot be controlled or when the liver ceases functioning, liver transplantation is necessary. Survival from liver transplantation has been improving over the 1990s, and the five-year survival rate is now around 80%, depending largely on the severity of disease and other medical problems in the recipient.[14] In the United States, the MELD score (online calculator)[15] is used to prioritize patients for transplantation. Transplantation necessitates the use of immune suppressants (cyclosporine or tacrolimus).

[edit] Decompensated cirrhosis In patients with previously stable cirrhosis, decompensation may occur due to various causes, such as constipation, infection (of any source), increased alcohol intake, medication, bleeding from esophageal varices or dehydration. It may take the form of any of the complications of cirrhosis listed above. Patients with decompensated cirrhosis generally require admission to hospital, with close monitoring of the fluid balance, mental status, and emphasis on adequate nutrition and medical treatment - often with diuretics, antibiotics, laxatives and/or enemas, thiamine and occasionally steroids, acetylcysteine and pentoxifylline. Administration of saline is generally avoided as it would add to the already high total body sodium content that typically occurs in cirrhosis.

[edit] Epidemiology Cirrhosis and chronic liver disease were the 10th leading cause of death for men and the 12th for women in the United States in 2001, killing about 27,000 people each year.[16] Also, the cost of cirrhosis in terms of human suffering, hospital costs, and lost productivity is high. Established cirrhosis has a 10-year mortality of 34-66%, largely dependent on the cause of the cirrhosis; alcoholic cirrhosis has a worse prognosis than primary biliary cirrhosis and cirrhosis due to hepatitis. The risk of death due to all causes is increased twelvefold; if one excludes the direct consequences of the liver disease, there is still a fivefold increased risk of death in all disease categories.[17] Little is known on modulators of cirrhosis risk, apart from other diseases that cause liver injury (such as the combination of alcoholic liver disease and chronic viral hepatitis, which may act synergistically in leading to cirrhosis). Studies have recently suggested that coffee consumption may protect against cirrhosis, especially alcoholic cirrhosis.

Diabetes mellitus From Wikipedia, the free encyclopedia

Jump to: navigation, search For the disease characterized by excretion of large amounts of very dilute urine, see diabetes insipidus. For diabetes mellitus in pets, see diabetes in cats and dogs. Diabetes mellitus Classification and external resources

Universal blue circle symbol for diabetes.[1]

ICD-10

E10.–E14.

ICD-9

250

MedlinePlus 001214 eMedicine MeSH

med/546 emerg/134 C18.452.394.750

Diabetes mellitus (IPA: /ˌdaɪəˈbiːtiːz/ or /ˌdaɪəˈbiːtəs/, /məˈlaɪtəs/ or / ˈmɛlətəs/), often referred to simply as diabetes (Ancient Greek: διαβαίνειν "to pass through"), is a syndrome of disordered metabolism, usually due to a combination of hereditary and environmental causes, resulting in abnormally high blood sugar levels (hyperglycemia).[2] Blood glucose levels are controlled by a complex interaction of multiple chemicals and hormones in the body, including the hormone insulin made in the beta cells of the pancreas. Diabetes mellitus refers to the group of diseases that lead to high blood glucose levels due to defects in either insulin secretion or insulin action. [3] Diabetes develops due to a diminished production of insulin (in type 1) or resistance to its effects (in type 2 and gestational).[4] Both lead to hyperglycaemia, which largely causes the acute signs of diabetes: excessive urine production, resulting compensatory thirst and increased fluid intake, blurred vision, unexplained weight loss, lethargy, and changes in energy metabolism. Monogenic forms, e.g. MODY, constitute 1-5 % of all cases.[5] All forms of diabetes have been treatable since insulin became medically available in 1921, but there is no cure. The injections by a syringe, insulin pump, or insulin pen deliver insulin, which is a basic treatment of type 1 diabetes. Type 2 is managed with a combination of dietary treatment, medications and insulin supplementation.

Diabetes and its treatments can cause many complications. Acute complications (hypoglycemia, ketoacidosis, or nonketotic hyperosmolar coma) may occur if the disease is not adequately controlled. Serious long-term complications include cardiovascular disease (doubled risk), chronic renal failure, retinal damage (which can lead to blindness), nerve damage (of several kinds), and microvascular damage, which may cause erectile dysfunction and poor wound healing. Poor healing of wounds, particularly of the feet, can lead to gangrene, and possibly to amputation. Adequate treatment of diabetes, as well as increased emphasis on blood pressure control and lifestyle factors (such as not smoking and maintaining a healthy body weight), may improve the risk profile of most of the chronic complications. In the developed world, diabetes is the most significant cause of adult blindness in the non-elderly and the leading cause of nontraumatic amputation in adults, and diabetic nephropathy is the main illness requiring renal dialysis in the United States.[6]

Diabetes mellitus Types of Diabetes Diabetes mellitus type 1 Diabetes mellitus type 2 Gestational diabetes Pre-diabetes: Impaired fasting glycaemia Impaired glucose tolerance Disease Management Diabetes management: •Diabetic diet •Anti-diabetic drugs •Conventional insulinotherapy •Intensive insulinotherapy Other Concerns Cardiovascular disease Diabetic comas: •Diabetic hypoglycemia •Diabetic ketoacidosis •Nonketotic hyperosmolar Diabetic myonecrosis Diabetic nephropathy Diabetic neuropathy Diabetic retinopathy Diabetes and pregnancy Blood tests Blood sugar Fructosamine Glucose tolerance test Glycosylated hemoglobin

Contents [hide] •

• • •

1 Classification o 1.1 Type 1 diabetes mellitus o 1.2 Type 2 diabetes mellitus o 1.3 Gestational diabetes o 1.4 Other types 2 Signs and symptoms 3 Genetics 4 Pathophysiology

• • • • •

5 Diagnosis 6 Screening 7 Prevention 8 Treatment and management 9 Cure o 9.1 Cures for type 1 diabetes o 9.2 Cures for type 2 diabetes 10 Prognosis o 10.1 Acute complications o 10.2 Chronic complications 11 Epidemiology 12 History 13 Social issues 14 See also 15 References

•

16 External links

• • • • •

•

Classification The term diabetes, without qualification, usually refers to diabetes mellitus, which is associated with excessive sweet urine (known as "glycosuria") but there are several rarer conditions also named diabetes. The most common of these is diabetes insipidus in which the urine is not sweet (insipidus meaning "without taste" in Latin); it can be caused by either kidney (nephrogenic DI) or pituitary gland (central DI) damage. The term "type 1 diabetes" has universally replaced several former terms, including childhood-onset diabetes, juvenile diabetes, and insulin-dependent diabetes (IDDM). Likewise, the term "type 2 diabetes" has replaced several former terms, including adultonset diabetes, obesity-related diabetes, and non-insulin-dependent diabetes (NIDDM). Beyond these two types, there is no agreed-upon standard nomenclature. Various sources have defined "type 3 diabetes" as, among others, gestational diabetes,[7] insulin-resistant type 1 diabetes (or "double diabetes"), type 2 diabetes which has progressed to require injected insulin, and latent autoimmune diabetes of adults (or LADA or "type 1.5" diabetes.[8]) There is also maturity onset diabetes of the young (MODY) which is a group of several single gene (monogenic) disorders with strong family histories that present as type 2 diabetes before 30 years of age.

Type 1 diabetes mellitus Main article: Diabetes mellitus type 1

Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas, leading to a deficiency of insulin. This type of diabetes can be further classified as immune-mediated or idiopathic. The majority of type 1 diabetes is of the immune-mediated variety, where beta cell loss is a T-cell mediated autoimmune attack.[3] There is no known preventive measure which can be taken against type 1 diabetes; it is about 10% of diabetes mellitus cases in North America and Europe (though this varies by geographical location), and is a higher percentage in some other areas. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. Type 1 diabetes can affect children or adults but was traditionally termed "juvenile diabetes" because it represents a majority of the diabetes cases in children. The principal treatment of type 1 diabetes, even in its earliest stages, is the delivery of artificial insulin via injection combined with careful monitoring of blood glucose levels using blood testing monitors. Without insulin, diabetic ketoacidosis often develops which may result in coma or death. Treatment emphasis is now also placed on lifestyle adjustments (diet and exercise) though these cannot reverse the progress of the disease. Apart from the common subcutaneous injections, it is also possible to deliver insulin by a pump, which allows continuous infusion of insulin 24 hours a day at preset levels, and the ability to program doses (a bolus) of insulin as needed at meal times. An inhaled form of insulin was approved by the FDA in January 2006, although it was discontinued for business reasons in October 2007. [9][10] Non-insulin treatments, such as monoclonal antibodies and stem-cell based therapies, are effective in animal models but have not yet completed clinical trials in humans.[11] Type 1 treatment must be continued indefinitely in essentially all cases. Treatment need not significantly impair normal activities, if sufficient patient training, awareness, appropriate care, discipline in testing and dosing of insulin is taken. However, treatment is burdensome for patients, insulin is replaced in a non-physiological manner, and this approach is therefore far from ideal. The average glucose level for the type 1 patient should be as close to normal (80–120 mg/dl, 4–6 mmol/l) as is safely possible. Some physicians suggest up to 140–150 mg/dl (7-7.5 mmol/l) for those having trouble with lower values, such as frequent hypoglycemic events. Values above 400 mg/dl (20 mmol/l) is sometimes accompanied by discomfort and frequent urination leading to dehydration. Values above 600 mg/dl (30 mmol/l) usually require medical treatment and may lead to ketoacidosis, although they are not immediately life-threatening. However, low levels of blood glucose, called hypoglycemia, may lead to seizures or episodes of unconsciousness and absolutely must be treated immediately, via emergency high-glucose gell placed in the patient's mouth or an injection of glucagon.

Type 2 diabetes mellitus Main article: diabetes mellitus type 2 Type 2 diabetes mellitus is characterized differently due to insulin resistance or reduced insulin sensitivity, combined with relatively reduced, and sometimes absolute, insulin

secretion. The defective responsiveness of body tissues to insulin almost certainly involves the insulin receptor in cell membranes. However, the specific defects are not known. Diabetes mellitus due to a known specific defect are classified separately. In the early stage of type 2 diabetes, the predominant abnormality is reduced insulin sensitivity, characterized by elevated levels of insulin in the blood. At this stage hyperglycemia can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce glucose production by the liver. As the disease progresses, the impairment of insulin secretion worsens, and therapeutic replacement of insulin often becomes necessary. There are numerous theories as to the exact cause and mechanism in type 2 diabetes. Central obesity (fat concentrated around the waist in relation to abdominal organs, but not subcutaneous fat) is known to predispose individuals to insulin resistance. Abdominal fat is especially active hormonally, secreting a group of hormones called adipokines that may possibly impair glucose tolerance. Obesity is found in approximately 55% of patients diagnosed with type 2 diabetes.[12] Other factors include aging (about 20% of elderly patients in North America have diabetes) and family history (type 2 is much more common in those with close relatives who have had it). In the last decade, type 2 diabetes has increasingly begun to affect children and adolescents, likely in connection with the increased prevalence of childhood obesity seen in recent decades in some places.[13] Environmental exposures may contribute to recent increases in the rate of type 2 diabetes. A positive correlation has been found between the concentration in the urine of bisphenol A, a constituent of polycarbonate plastic, and the incidence of type 2 diabetes.[14] Type 2 diabetes may go unnoticed for years because visible symptoms are typically mild, non-existent or sporadic, and usually there are no ketoacidotic episodes. However, severe long-term complications can result from unnoticed type 2 diabetes, including renal failure due to diabetic nephropathy, vascular disease (including coronary artery disease), vision damage due to diabetic retinopathy, loss of sensation or pain due to diabetic neuropathy, liver damage from non-alcoholic steatohepatitis and heart failure from diabetic cardiomyopathy. Type 2 diabetes is usually first treated by increasing physical activity, decreasing carbohydrate intake, and losing weight. These can restore insulin sensitivity even when the weight loss is modest, for example around 5 kg (10 to 15 lb), most especially when it is in abdominal fat deposits. It is sometimes possible to achieve long-term, satisfactory glucose control with these measures alone. However, the underlying tendency to insulin resistance is not lost, and so attention to diet, exercise, and weight loss must continue. The usual next step, if necessary, is treatment with oral antidiabetic drugs. Insulin production is initially only moderately impaired in type 2 diabetes, so oral medication (often used in various combinations) can be used to improve insulin production (e.g., sulfonylureas), to regulate inappropriate release of glucose by the liver and attenuate insulin resistance to some extent (e.g., metformin), and to substantially attenuate insulin resistance (e.g., thiazolidinediones). According to one study, overweight patients treated with metformin compared with diet alone, had relative risk reductions of 32% for any

diabetes endpoint, 42% for diabetes related death and 36% for all cause mortality and stroke.[15] Oral medication may eventually fail due to further impairment of beta cell insulin secretion. At this point, insulin therapy is necessary to maintain normal or near normal glucose levels.

Gestational diabetes Main article: Gestational diabetes Gestational diabetes mellitus (GDM) resembles type 2 diabetes in several respects, involving a combination of relatively inadequate insulin secretion and responsiveness. It occurs in about 2%–5% of all pregnancies and may improve or disappear after delivery. Gestational diabetes is fully treatable but requires careful medical supervision throughout the pregnancy. About 20%–50% of affected women develop type 2 diabetes later in life. Even though it may be transient, untreated gestational diabetes can damage the health of the fetus or mother. Risks to the baby include macrosomia (high birth weight), congenital cardiac and central nervous system anomalies, and skeletal muscle malformations. Increased fetal insulin may inhibit fetal surfactant production and cause respiratory distress syndrome. Hyperbilirubinemia may result from red blood cell destruction. In severe cases, perinatal death may occur, most commonly as a result of poor placental perfusion due to vascular impairment. Induction may be indicated with decreased placental function. A cesarean section may be performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystocia. A 2008 study completed in the U.S. found that more American women are entering pregnancy with preexisting diabetes. In fact the rate of diabetes in expectant mothers has more than doubled in the past 6 years. [16] This is particularly problematic as diabetes raises the risk of complications during pregnancy, as well as increasing the potential that the children of diabetic mothers will also become diabetic in the future.

Other types Most cases of diabetes mellitus fall into the two broad etiologic categories of type 1 or type 2 diabetes. However, many types of diabetes mellitus have known specific causes, and thus fall into separate categories as diabetes due to a specifc cause. As more research is done into diabetes, many patients who were previously diagnosed as type 1 or type 2 diabetes will be reclassified as diabetes due to their known specific cause. Some cases of diabetes are caused by the body's tissue receptors not responding to insulin (even when insulin levels are normal, which is what separates it from type 2 diabetes); this form is very uncommon. Genetic mutations (autosomal or mitochondrial) can lead to defects in beta cell function. Abnormal insulin action may also have been genetically determined in some cases. Any disease that causes extensive damage to the pancreas may lead to diabetes (for example, chronic pancreatitis and cystic fibrosis). Diseases associated with excessive secretion of insulin-antagonistic hormones can cause diabetes

(which is typically resolved once the hormone excess is removed). Many drugs impair insulin secretion and some toxins damage pancreatic beta cells. The ICD-10 (1992) diagnostic entity, malnutrition-related diabetes mellitus (MRDM or MMDM, ICD-10 code E12), was deprecated by the World Health Organization when the current taxonomy was introduced in 1999.[4]

Signs and symptoms The classical triad of diabetes symptoms is polyuria, polydipsia and polyphagia, which are, respectively, frequent urination, increased thirst and consequent increased fluid intake, and increased appetite. Symptoms may develop quite rapidly (weeks or months) in type 1 diabetes, particularly in children. However, in type 2 diabetes symptoms usually develop much more slowly and may be subtle or completely absent. Type 1 diabetes may also cause a rapid yet significant weight loss (despite normal or even increased eating) and irreducible fatigue. All of these symptoms except weight loss can also manifest in type 2 diabetes in patients whose diabetes is poorly controlled. When the glucose concentration in the blood is raised beyond its renal threshold, reabsorption of glucose in the proximal renal tubuli is incomplete, and part of the glucose remains in the urine (glycosuria). This increases the osmotic pressure of the urine and inhibits reabsorption of water by the kidney, resulting in increased urine production (polyuria) and increased fluid loss. Lost blood volume will be replaced osmotically from water held in body cells and other body compartments, causing dehydration and increased thirst. Prolonged high blood glucose causes glucose absorption, which leads to changes in the shape of the lenses of the eyes, resulting in vision changes; sustained sensible glucose control usually returns the lens to its original shape. Blurred vision is a common complaint leading to a diabetes diagnosis; type 1 should always be suspected in cases of rapid vision change, whereas with type 2 change is generally more gradual, but should still be suspected. Patients (usually with type 1 diabetes) may also initially present with diabetic ketoacidosis (DKA), an extreme state of metabolic dysregulation characterized by the smell of acetone on the patient's breath; a rapid, deep breathing known as Kussmaul breathing; polyuria; nausea; vomiting and abdominal pain; and any of many altered states of consciousness or arousal (such as hostility and mania or, equally, confusion and lethargy). In severe DKA, coma may follow, progressing to death. Diabetic ketoacidosis is a medical emergency and requires immediate hospitalization. A rarer but equally severe possibility is hyperosmolar nonketotic state, which is more common in type 2 diabetes and is mainly the result of dehydration due to loss of body water. Often, the patient has been drinking extreme amounts of sugar-containing drinks, leading to a vicious circle in regard to the water loss.

Genetics Both type 1 and type 2 diabetes are at least partly inherited. Type 1 diabetes appears to be triggered by some (mainly viral) infections, or less commonly, by stress or environmental exposure (such as exposure to certain chemicals or drugs). There is a genetic element in individual susceptibility to some of these triggers which has been traced to particular HLA genotypes (i.e., the genetic "self" identifiers relied upon by the immune system). However, even in those who have inherited the susceptibility, type 1 diabetes mellitus seems to require an environmental trigger. A small proportion of people with type 1 diabetes carry a mutated gene that causes maturity onset diabetes of the young (MODY). There is a stronger inheritance pattern for type 2 diabetes. Those with first-degree relatives with type 2 have a much higher risk of developing type 2, increasing with the number of those relatives. Concordance among monozygotic twins is close to 100%, and about 25% of those with the disease have a family history of diabetes. Genes significantly associated with developing type 2 diabetes, include TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX.[17] KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11), encodes the islet ATPsensitive potassium channel Kir6.2, and TCF7L2 (transcription factor 7–like 2) regulates proglucagon gene expression and thus the production of glucagon-like peptide-1.[3] Moreover, obesity (which is an independent risk factor for type 2 diabetes) is strongly inherited.[18] Various hereditary conditions may feature diabetes, for example myotonic dystrophy and Friedreich's ataxia. Wolfram's syndrome is an autosomal recessive neurodegenerative disorder that first becomes evident in childhood. It consists of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, hence the acronym DIDMOAD.[19]

Pathophysiology Mechanism of insulin release in normal pancreatic beta cells. Insulin production is more or less constant within the beta cells, irrespective of blood glucose levels. It is stored within vacuoles pending release, via exocytosis, which is primarily triggered by food, chiefly food containing absorbable glucose. The chief trigger is a rise in blood glucose levels after eating Insulin is the principal hormone that regulates uptake of glucose from the blood into most cells (primarily muscle and fat cells, but not central nervous system cells). Therefore deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus. Most of the carbohydrates in food are converted within a few hours to the monosaccharide glucose, the principal carbohydrate found in blood and used by the body

as fuel. The most significant exceptions are fructose, most disaccharides (except sucrose and in some people lactose), and all more complex polysaccharides, with the outstanding exception of starch. Insulin is released into the blood by beta cells (β-cells), found in the Islets of Langerhans in the pancreas, in response to rising levels of blood glucose, typically after eating. Insulin is used by about two-thirds of the body's cells to absorb glucose from the blood for use as fuel, for conversion to other needed molecules, or for storage. Insulin is also the principal control signal for conversion of glucose to glycogen for internal storage in liver and muscle cells. Lowered glucose levels result both in the reduced release of insulin from the beta cells and in the reverse conversion of glycogen to glucose when glucose levels fall. This is mainly controlled by the hormone glucagon which acts in an opposite manner to insulin. Glucose thus recovered by the liver re-enters the bloodstream; muscle cells lack the necessary export mechanism. Higher insulin levels increase some anabolic ("building up") processes such as cell growth and duplication, protein synthesis, and fat storage. Insulin (or its lack) is the principal signal in converting many of the bidirectional processes of metabolism from a catabolic to an anabolic direction, and vice versa. In particular, a low insulin level is the trigger for entering or leaving ketosis (the fat burning metabolic phase). If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity or resistance), or if the insulin itself is defective, then glucose will not be absorbed properly by those body cells that require it nor will it be stored appropriately in the liver and muscles. The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as acidosis.

Diagnosis The diagnosis of type 1 diabetes, and many cases of type 2, is usually prompted by recent-onset symptoms of excessive urination (polyuria) and excessive thirst (polydipsia), often accompanied by weight loss. These symptoms typically worsen over days to weeks; about a quarter of people with new type 1 diabetes have developed some degree of diabetic ketoacidosis by the time the diabetes is recognized. The diagnosis of other types of diabetes is usually made in other ways. These include ordinary health screening; detection of hyperglycemia during other medical investigations; and secondary symptoms such as vision changes or unexplainable fatigue. Diabetes is often detected when a person suffers a problem that is frequently caused by diabetes, such as a heart attack, stroke, neuropathy, poor wound healing or a foot ulcer, certain eye problems, certain fungal infections, or delivering a baby with macrosomia or hypoglycemia. Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:[4] •

fasting plasma glucose level at or above 126 mg/dL (7.0 mmol/l).

• •

plasma glucose at or above 200 mg/dL (11.1 mmol/l) two hours after a 75 g oral glucose load as in a glucose tolerance test. symptoms of hyperglycemia and casual plasma glucose at or above 200 mg/dL (11.1 mmol/l).

A positive result, in the absence of unequivocal hyperglycemia, should be confirmed by a repeat of any of the above-listed methods on a different day. Most physicians prefer to measure a fasting glucose level because of the ease of measurement and the considerable time commitment of formal glucose tolerance testing, which takes two hours to complete. According to the current definition, two fasting glucose measurements above 126 mg/dL (7.0 mmol/l) is considered diagnostic for diabetes mellitus. Patients with fasting glucose levels from 100 to 125 mg/dL (6.1 and 7.0 mmol/l) are considered to have impaired fasting glucose. Patients with plasma glucose at or above 140 mg/dL or 7.8 mmol/l, but not over 200, two hours after a 75 g oral glucose load are considered to have impaired glucose tolerance. Of these two pre-diabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes mellitus as well as cardiovascular disease.[20] While not used for diagnosis, an elevated level of glucose irreversibly bound to hemoglobin (termed glycosylated hemoglobin or HbA1c) of 6.0% or higher (the 2003 revised U.S. standard) is considered abnormal by most labs; HbA1c is primarily used as a treatment-tracking test reflecting average blood glucose levels over the preceding 90 days (approximately). However, some physicians may order this test at the time of diagnosis to track changes over time. The current recommended goal for HbA1c in patients with diabetes is <7.0%, which is considered good glycemic control, although some guidelines are stricter (<6.5%). People with diabetes who have HbA1c levels within this range have a significantly lower incidence of complications from diabetes, including retinopathy and diabetic nephropathy.[21][22]

Screening Diabetes screening is recommended for many people at various stages of life, and for those with any of several risk factors. The screening test varies according to circumstances and local policy, and may be a random blood glucose test, a fasting blood glucose test, a blood glucose test two hours after 75 g of glucose, or an even more formal glucose tolerance test. Many healthcare providers recommend universal screening for adults at age 40 or 50, and often periodically thereafter. Earlier screening is typically recommended for those with risk factors such as obesity, family history of diabetes, highrisk ethnicity (Hispanic, Native American, Afro-Caribbean, Pacific Islander).[23][24] Many medical conditions are associated with diabetes and warrant screening. A partial list includes: high blood pressure, elevated cholesterol levels, coronary artery disease, past gestational diabetes, polycystic ovary syndrome, chronic pancreatitis, fatty liver, hemochromatosis, cystic fibrosis, several mitochondrial neuropathies and myopathies, myotonic dystrophy, Friedreich's ataxia, some of the inherited forms of neonatal

hyperinsulinism. The risk of diabetes is higher with chronic use of several medications, including high-dose glucocorticoids, some chemotherapy agents (especially Lasparaginase), as well as some of the antipsychotics and mood stabilizers (especially phenothiazines and some atypical antipsychotics). People with a confirmed diagnosis of diabetes are tested routinely for complications. This includes yearly urine testing for microalbuminuria and examination of the retina of the eye for retinopathy. In the UK, systematic screening for diabetic retinopathy, which can be effectively treated if detected at an early stage, has helped reduce visual impairment in people with diabetes since its implementation.[citation needed]

Prevention Type 1 diabetes risk is known to depend upon a genetic predisposition based on HLA types (particularly types DR3 and DR4), an unknown environmental trigger (suspected to be an infection, although none has proven definitive in all cases), and an uncontrolled autoimmune response that attacks the insulin producing beta cells.[25] Some research has suggested that breastfeeding decreased the risk in later life; [26][27] various other nutritional risk factors are being studied, but no firm evidence has been found. [28] Giving children 2000 IU of Vitamin D during their first year of life is associated with reduced risk of type 1 diabetes, though the causal relationship is obscure.[29] Children with antibodies to beta cell proteins (ie, at early stages of an immune reaction to them) but no overt diabetes, and treated with vitamin B-3 (niacin), had less than half the diabetes onset incidence in a 7-year time span as did the general population, and an even lower incidence relative to those with antibodies as above, but who received no vitamin B3.[30] Type 2 diabetes risk can be reduced in many cases by making changes in diet and increasing physical activity.[31][32] The American Diabetes Association (ADA) recommends maintaining a healthy weight, getting at least 2½ hours of exercise per week (several brisk sustained walks appear sufficient), having a modest fat intake, and eating sufficient fiber (eg, from whole grains). The ADA does not recommend alcohol consumption as a preventive, but it is interesting to note that moderate alcohol intake may reduce the risk (though heavy consumption absolutely and clearly increases damage to bodily systems significantly); a similarly confused connection between low dose alcohol consumption and heart disease is termed the French Paradox. There is inadequate evidence that eating foods of low glycemic index is clinically helpful despite recommendations and suggested diets emphasizing this approach.[33] There are numerous studies which suggest connections between some aspects of Type II diabetes with ingestion of certain foods or with some drugs. Some studies have shown delayed progression to diabetes in predisposed patients through prophylactic use of metformin,[32] rosiglitazone,[34] or valsartan.[35] In patients on hydroxychloroquine for rheumatoid arthritis, incidence of diabetes was reduced by 77% though causal

mechanisms are unclear.[36] Breastfeeding may also be associated with the prevention of type 2 of the disease in mothers.[37] Clear evidence for these and any of many other connections between foods and supplements and diabetes is sparse to date; none, despite secondary claims for (or against), is sufficiently well established to justify as a standard clinical approach.

Treatment and management Main article: Diabetes management Diabetes mellitus is currently a chronic disease, without a cure, and medical emphasis must necessarily be on managing/avoiding possible short-term as well as long-term diabetes-related problems. There is an exceptionally important role for patient education, dietetic support, sensible exercise, self monitoring of blood glucose, with the goal of keeping both short-term blood glucose levels, and long term levels as well, within acceptable bounds. Careful control is needed to reduce the risk of long term complications. This is theoretically achievable with combinations of diet, exercise and weight loss (type 2), various oral diabetic drugs (type 2 only), and insulin use (type 1 and for type 2 not responding to oral medications, mostly those with extended duration diabetes). In addition, given the associated higher risks of cardiovascular disease, lifestyle modifications should be undertaken to control blood pressure[38] and cholesterol by exercising more, smoking less or ideally not at all, consuming an appropriate diet, wearing diabetic socks, wearing diabetic shoes, and if necessary, taking any of several drugs to reduce blood pressure. Many Type 1 treatments include combination use of regular or NPH insulin, and/or synthetic insulin analogs (eg, Humalog, Novolog or Apidra) in combinations such as Lantus/Levemir and Humalog, Novolog or Apidra. Another Type 1 treatment option is the use of the insulin pump (eg, from Deltec Cozmo, Animas, Medtronic Minimed, Insulet Omnipod, or ACCU-CHEK). A blood lancet is used to pierce the skin (typically of a finger), in order to draw blood to test it for sugar levels. In countries using a general practitioner system, such as the United Kingdom, care may take place mainly outside hospitals, with hospital-based specialist care used only in case of complications, difficult blood sugar control, or research projects. In other circumstances, general practitioners and specialists share care of a patient in a team approach. Optometrists, podiatrists/chiropodists, dietitians, physiotherapists, nursing specialists (eg, DSNs (Diabetic Specialist Nurse)), nurse practitioners, or Certified Diabetes Educators, may jointly provide multidisciplinary expertise. In countries where patients must provide their own health care (i.e., in the developed world, the US, and in much of the undeveloped world), the impact of out-of-pocket costs of adequate diabetic care can be very high. In addition to the medications and supplies needed, patients are often advised to receive regular consultation from a physician (e.g., at least every three to six months).

Cure

Cures for type 1 diabetes Main article: Cure for diabetes mellitus type 1 There is no practical cure, at this time, for type 1 diabetes. The fact that type 1 diabetes is due to the failure of one of the cell types of a single organ with a relatively simple function (i.e. the failure of the veta cells in the Islets of Langerhans) has led to the study of several possible schemes to cure this form of diabetes mostly by replacing the pancreas or just the beta cells.[39] Only those type 1 diabetics who have received either a pancreas or a kidney-pancreas transplant (often when they have developed diabetic kidney disease (ie, nephropathy) and become insulin-independent) may now be considered "cured" from their diabetes. A simultaneous pancreas-kidney transplant is a promising solution, showing similar or improved survival rates over a kidney transplant alone.[40] Still, they generally remain on long-term immunosuppressive drugs and there is a possibility that the immune system will mount a host versus graft response against the transplanted organ.[39] Transplants of exogenous beta cells have been performed experimentally in both mice and humans, but this measure is not yet practical in regular clinical practice partly due to the limited number of beta cell donors. Thus far, like any such transplant, it has provoked an immune reaction and long-term immunosuppressive drugs have been needed to protect the transplanted tissue.[41] An alternative technique has been proposed to place transplanted beta cells in a semi-permeable container, isolating and protecting them from the immune system. Stem cell research has also been suggested as a potential avenue for a cure since it may permit regrowth of Islet cells which are genetically part of the treated individual, thus perhaps eliminating the need for immuno-suppressants.[39] This has been done in mice, and a 2007 trial of 15 newly diagnosed patients with type 1 diabetes treated with stem cells raised from their own bone marrow after immune suppression showed that the majority did not require any insulin treatment for prolonged periods of time.[42] Microscopic or nanotechnological approaches are under investigation as well, in one proposed case with implanted stores of insulin metered out by a rapid response valve sensitive to blood glucose levels. At least two approaches have been demonstrated in vitro. These are, in some sense, closed-loop insulin pumps.

Cures for type 2 diabetes Type 2 has had no definitive cure, although recently it has been shown that a type of gastric bypass surgery can normalize blood glucose levels in 80-100% of severely obese patients with diabetes. The precise causal mechanisms are being intensively researched; its results are not simply attributable to weight loss, as the improvement in blood sugars precedes any change in body mass. This approach may become a standard treatment for some people with type 2 diabetes in the relatively near future.[43] This surgery has the additional benefit of reducing the death rate from all causes by up to 40% in severely obese people.[44] A small number of normal to moderately obese patients with type 2 diabetes have successfully undergone similar operations.[45][46]

Prognosis Patient education, understanding, and participation is vital since the complications of diabetes are far less common and less severe in people who have well-controlled blood sugar levels.[47][48] Wider health problems accelerate the deleterious effects of diabetes. These include smoking, elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise. According to a study, women with high blood pressure have a threefold risk of developing diabetes. Anecdotal evidence suggests that some of those with type 2 diabetes who exercise regularly, lose weight, and eat healthy diets may be able to keep some of the disease or some of the effects of the disease in 'remission.' Certainly these tips can help prevent people predisposed to type 2 diabetes and those at pre-diabetic stages from actually developing the disorder as it helps restore insulin sensitivity. However patients should talk to their doctors about this for real expectations before undertaking it (esp. to avoid hypoglycemia or other complications); few people actually seem to go into total 'remission,' but some may find they need less of their insulin medications since the body tends to have lower insulin requirements during and shortly following exercise. Regardless of whether it works that way or not for an individual, there are certainly other benefits to this healthy lifestyle for both diabetics and nondiabetics. The way diabetes is managed changes with age. Insulin production decreases because of age-related impairment of pancreatic beta cells. Additionally, insulin resistance increases because of the loss of lean tissue and the accumulation of fat, particularly intra-abdominal fat, and the decreased tissue sensitivity to insulin. Glucose tolerance progressively declines with age, leading to a high prevalence of type 2 diabetes and postchallenge hyperglycemia in the older population.[49] Age-related glucose intolerance in humans is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people. [50] Treatment goals for older patients with diabetes vary with the individual, and take into account health status, as well as life expectancy, level of dependence, and willingness to adhere to a treatment regimen.[51]

Acute complications Main articles: Diabetic ketoacidosis, nonketotic hyperosmolar coma, hypoglycemia, and diabetic coma Diabetic ketoacidosis Diabetic ketoacidosis (DKA) is an acute and dangerous complication that is always a medical emergency. Low insulin levels cause the liver to turn to fat for fuel (ie, ketosis); ketone bodies are intermediate substrates in that metabolic sequence. This is normal when periodic, but can become a serious problem if sustained. Elevated levels of ketone bodies in the blood decrease the blood's pH, leading to DKA. On presentation at hospital, the patient in DKA is typically dehydrated, and breathing rapidly and deeply. Abdominal pain is common and may be severe. The level of consciousness is typically normal until late in the process, when lethargy may progress to coma. Ketoacidosis can easily become severe

enough to cause hypotension, shock, and death. Urine analysis will reveal significant levels of ketone bodies (which have exceeded their renal threshold blood levels to appear in the urine, often before other overt symptoms). Prompt, proper treatment usually results in full recovery, though death can result from inadequate or delayed treatment, or from complications (dg, brain edema). DKA is always a medical emergency and requires medical attention. Ketoacidosis is much more common in type 1 diabetes than type 2. Hyperglycemia hyperosmolar state Hyperosmolar nonketotic state (HNS) is an acute complication sharing many symptoms with DKA, but an entirely different origin and different treatment. A person with very high (usually considered to be above 300 mg/dl (16 mmol/l)) blood glucose levels, water is osmotically drawn out of cells into the blood and the kidneys eventually begin to dump glucose into the urine. This results in loss of water and an increase in blood osmolarity. If fluid is not replaced (by mouth or intravenously), the osmotic effect of high glucose levels, combined with the loss of water, will eventually lead to dehydration. The body's cells become progressively dehydrated as water is taken from them and excreted. Electrolyte imbalances are also common and are always dangerous. As with DKA, urgent medical treatment is necessary, commonly beginning with fluid volume replacement. Lethargy may ultimately progress to a coma, though this is more common in type 2 diabetes than type 1. Hypoglycemia Hypoglycemia, or abnormally low blood glucose, is an acute complication of several diabetes treatments. It is rare otherwise, either in diabetic or non-diabetic patients. The patient may become agitated, sweaty, and have many symptoms of sympathetic activation of the autonomic nervous system resulting in feelings akin to dread and immobilized panic. Consciousness can be altered or even lost in extreme cases, leading to coma, seizures, or even brain damage and death. In patients with diabetes, this may be caused by several factors, such as too much or incorrectly timed insulin, too much or incorrectly timed exercise (exercise decreases insulin requirements) or not enough food (specifically glucose containing carbohydrates). The variety of interactions makes cause identification difficult in many instances. It is more accurate to note that iatrogenic hypoglycemia is typically the result of the interplay of absolute (or relative) insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine are the primary glucose counterregulatory factors that normally prevent or (more or less rapidly) correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation. Furthermore, reduced sympathoadrenal responses can cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits

that recent incidents of hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. In many cases (but not all), short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in affected patients, although this is easier in theory than in clinical experience. In most cases, hypoglycemia is treated with sugary drinks or food. In severe cases, an injection of glucagon (a hormone with effects largely opposite to those of insulin) or an intravenous infusion of dextrose is used for treatment, but usually only if the person is unconscious. In any given incident, glucogon will only work once as it uses stored liver glycogen as a glucose source; in the absence of such stores, glucagon is largely ineffective. In hospitals, intravenous dextrose is often used.

Chronic complications Vascular disease Chronic elevation of blood glucose level leads to damage of blood vessels (angiopathy). The endothelial cells lining the blood vessels take in more glucose than normal, since they don't depend on insulin. They then form more surface glycoproteins than normal, and cause the basement membrane to grow thicker and weaker. In diabetes, the resulting problems are grouped under "microvascular disease" (due to damage to small blood vessels) and "macrovascular disease" (due to damage to the arteries).

Image of fundus showing scatter laser surgery for diabetic retinopathy The damage to small blood vessels leads to a microangiopathy, which can cause one or more of the following: •

•

Diabetic retinopathy, growth of friable and poor-quality new blood vessels in the retina as well as macular edema (swelling of the macula), which can lead to severe vision loss or blindness. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US. Diabetic neuropathy, abnormal and decreased sensation, usually in a 'glove and stocking' distribution starting with the feet but potentially in other nerves, later often fingers and hands. When combined with damaged blood vessels this can lead to diabetic foot (see below). Other forms of diabetic neuropathy may present

•

•

as mononeuritis or autonomic neuropathy. Diabetic amyotrophy is muscle weakness due to neuropathy. Diabetic nephropathy, damage to the kidney which can lead to chronic renal failure, eventually requiring dialysis. Diabetes mellitus is the most common cause of adult kidney failure worldwide in the developed world. Diabetic cardiomyopathy, damage to the heart, leading to diastolic dysfunction and eventually heart failure.

Macrovascular disease leads to cardiovascular disease, to which accelerated atherosclerosis is a contributor: • • • •

Coronary artery disease, leading to angina or myocardial infarction ("heart attack") Stroke (mainly the ischemic type) Peripheral vascular disease, which contributes to intermittent claudication (exertion-related leg and foot pain) as well as diabetic foot. Diabetic myonecrosis ('muscle wasting')

Diabetic foot, often due to a combination of sensory neuropathy (numbness or insensitivity) and vascular damage, increase rates of skin ulcers and infection and, in serious cases, necrosis and gangrene. It is why diabetics are prone to leg and foot infections and why it takes longer for them to heal from leg and foot wounds. It is the most common cause of non-traumatic adult amputation, usually of toes and or feet, in the developed world. Carotid artery stenosis does not occur more often in diabetes, and there appears to be a lower prevalence of abdominal aortic aneurysm. However, diabetes does cause higher morbidity, mortality and operative risks with these conditions.[52] Diabetic encephalopathy[53] is the increased cognitive decline and risk of dementia observed in diabetes. Various mechanisms are proposed, including alterations to the vascular supply of the brain and the interaction of insulin with the brain itself.[54].

Epidemiology In 2000, according to the World Health Organization, at least 171 million people worldwide suffer from diabetes, or 2.8% of the population.[55] Its incidence is increasing rapidly, and it is estimated that by the year 2030, this number will almost double.[55] Diabetes mellitus occurs throughout the world, but is more common (especially type 2) in the more developed countries. The greatest increase in prevalence is, however, expected to occur in Asia and Africa, where most patients will likely be found by 2030.[55] The increase in incidence of diabetes in developing countries follows the trend of urbanization and lifestyle changes, perhaps most importantly a "Western-style" diet. This has suggested an environmental (i.e., dietary) effect, but there is little understanding of the mechanism(s) at present, though there is much speculation, some of it most compellingly presented.[55]

For at least 20 years, diabetes rates in North America have been increasing substantially. In 2005 there were about 20.8 million people with diabetes in the United States alone. According to the American Diabetes Association, there are about 6.2 million people undiagnosed and about 41 million people that would be considered prediabetic.[56] However, the criteria for diagnosing diabetes in the USA mean that it is more readily diagnosed than in some other countries. The Centers for Disease Control has termed the change an epidemic.[57] The National Diabetes Information Clearinghouse estimates that diabetes costs $132 billion in the United States alone every year. About 5%–10% of diabetes cases in North America are type 1, with the rest being type 2. The fraction of type 1 in other parts of the world differs; this is likely due to both differences in the rate of type 1 and differences in the rate of other types, most prominently type 2. Most of this difference is not currently understood. The American Diabetes Association point out the 2003 assessment of the National Center for Chronic Disease Prevention and Health Promotion (Centers for Disease Control and Prevention) that 1 in 3 Americans born after 2000 will develop diabetes in their lifetime.[58][56] According to the American Diabetes Association, approximately 18.3% (8.6 million) of Americans age 60 and older have diabetes. [59] Diabetes mellitus prevalence increases with age, and the numbers of older persons with diabetes are expected to grow as the elderly population increases in number. The National Health and Nutrition Examination Survey (NHANES III) demonstrated that, in the population over 65 years old, 18% to 20% have diabetes, with 40% having either diabetes or its precursor form of impaired glucose tolerance.[49] Indigenous populations in first world countries have a higher prevalence and increasing incidence of diabetes than their corresponding non-indigenous populations. In Australia the age-standardised prevalence of self-reported diabetes in Indigenous Australians is almost 4 times that of non-indigenous Australians.[60] Preventative community health programs such as Sugar Man (diabetes education) are showing some success in tackling this problem.

Cushing's syndrome From Wikipedia, the free encyclopedia

Jump to: navigation, search "Cushing's" redirects here. For the circulatory reflex, see Cushing reflex. For the related three-part condition, see Cushing's triad. Cushing's syndrome Classification and external resources

Cortisol

ICD-10

E24.

ICD-9

255.0

DiseasesDB

3242

MedlinePlus

000410

eMedicine

med/485

MeSH

D003480

Cushing's syndrome (also called hyperadrenocorticism) is an endocrine disorder caused by high levels of cortisol in the blood. This hypercortisolism can be caused by intake of glucocorticoids, or by tumors that produce cortisol or ACTH.[1] Cushing's disease refers to one specific cause, namely an adenoma in the pituitary gland that produces large amounts of ACTH which in turn elevates cortisol. Cushing's syndrome is not confined to humans and is also a relatively common condition in domestic dogs and horses. It was described by American Dr. Harvey Cushing in 1932.[2]

Contents [hide] • • • • • • • • •

1 Classification and Etiology 2 Signs and symptoms 3 Diagnosis 4 Pathophysiology 5 Treatment 6 Epidemiology 7 Hyperadrenocorticism in domestic animals 8 See also 9 References

•

10 External links

[edit] Classification and Etiology

There are several possible causes of Cushing's syndrome. The most common is exogenous administration of glucocorticoids prescribed by physicians to treat other diseases (called iatrogenic Cushing's). This can be an effect of steroid treatment of a variety of disorders such as asthma and rheumatoid arthritis, or in immunosuppression after an organ transplant. Administration of synthetic ACTH is also possible, but ACTH is less often prescribed due to cost and lesser utility. Endogenous Cushing syndrome results from some derangement of the body's own system of secreting cortisol. Normally, ACTH is released from the pituitary gland when necessary to stimulate the release of cortisol from the adrenal glands. In pituitary Cushing's, a benign pituitary adenoma secretes ACTH. This is also known as Cushing's disease and is responsible for 65% of endogenous Cushing's. In adrenal Cushing's, excess cortisol is produced by adrenal gland tumors, hyperplastic adrenal glands, or adrenal glands with nodular adrenal hyperplasia. Finally, tumors outside the normal pituitary-adrenal system can produce ACTH that affects the adrenal glands. This final etiology is called ectopic or paraneoplastic Cushing's and is seen in diseases like small cell lung cancer. Cushing's syndrome can also be sub-classified according to whether or not the excess cortisol is dependent on increased ACTH. ACTH-dependent Cushing's is driven by increased ACTH and includes exogenous ACTH administration as well as pituitary and ectopic Cushing's. ACTH-independent Cushing's shows increased cortisol, but the ACTH is not elevated but rather decreased due to negative feedback. It can be caused by exogenous administration of glucocorticoids or by adrenal adenoma, carcinoma, or nodular hyperplasia.

[edit] Signs and symptoms Symptoms include rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity), a round face often referred to as a "moon face," excess sweating, telangiectasia (dilation of capillaries), thinning of the skin (which causes easy bruising) and other mucous membranes, purple or red striae (the weight gain in Cushing's stretches the skin, which is thin and weakened, causing it to hemorrhage) on the trunk, buttocks, arms, legs or breasts, proximal muscle weakness (hips, shoulders), and hirsutism (facial male-pattern hair growth). A common sign is the growth of fat pads along the collar bone and on the back of the neck (buffalo hump) (known as a lipodystrophy). The excess cortisol may also affect other endocrine systems and cause, for example, insomnia, reduced libido, impotence, amenorrhoea and infertility. Patients frequently suffer various psychological disturbances, ranging from euphoria to psychosis. Depression and anxiety are also common.[3] Other signs include polyuria (and accompanying polydipsia), persistent hypertension (due to cortisol's enhancement of epinephrine's vasoconstrictive effect) and insulin resistance (especially common in ectopic ACTH production), leading to hyperglycemia (high blood sugar) which can lead to diabetes mellitus. Untreated Cushing's syndrome can lead to heart disease and increased mortality. Cushing's syndrome due to excess ACTH may also

result in hyperpigmentation. This is due to Melanocyte-Stimulating Hormone production as a byproduct of ACTH synthesis from Pro-opiomelanocortin (POMC). Cortisol can also exhibit mineralcorticoid activity in high concentrations, worsening the hypertension and leading to hypokalemia (common in ectopic ACTH secretion). Furthermore, gastrointestinal disturbances, opportunistic infections and impaired wound healing (cortisol is a stress hormone, so it depresses the immune and inflammatory responses). Osteoporosis is also an issue in Cushing's Syndrome since, as mentioned before, cortisol evokes a stress-like response. The body's maintenance of bone (and other tissues) is therefore no longer one of its main priorities, so to speak. It is also important to note that Cushing's may elicit hirsutism (male-pattern hair growth in a female) and oligomenorrhea (decreased frequency of menstruation) due to elevations in androgens (male sex hormones), normally at low levels in women. The syndrome in horses leads to weight loss, polyuria and polydipsia and may cause laminitis.

[edit] Diagnosis When Cushing's is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offer equal detection rates.[4] Dexamethasone is a glucocorticoid and simulates the effects of cortisol, including negative feedback on the pituitary gland. When dexamethasone is administered and a blood sample is tested, high cortisol would be indicative of Cushing's syndrome because there is an ectopic source of cortisol or ACTH (eg: adrenal adenoma) that is not inhibited by the dexamethasone. A novel approach, recently cleared by the US FDA, is sampling cortisol in saliva over 24 hours, which may be equally sensitive, as late night levels of salivary cortisol are high in Cushingoid patients. Other pituitary hormone levels may need to be ascertained. Performing a physical examination to determine any visual field defect may be necessary if a pituitary lesion is suspected, which may compress the optic chiasm causing typical bitemporal hemianopia. When any of these tests are positive, CT scanning of the adrenal gland and MRI of the pituitary gland are performed to detect the presence of any adrenal or pituitary adenomas or incidentalomas (the incidental discovery of harmless lesions). Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary. Very rarely, determining the cortisol levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus sampling) is necessary.

[edit] Pathophysiology Both the hypothalamus and the pituitary gland are in the brain. The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol.

Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland. Strictly, Cushing's syndrome refers to excess cortisol of any etiology. One of the causes of Cushing's syndrome is a cortisol secreting adenoma in the cortex of the adrenal gland. The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low. Cushing's disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotrophic pituitary adenoma. This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because a tumor causes the pituitary to be unresponsive to negative feedback from high cortisol levels.

[edit] Treatment Most Cushing's syndrome cases are caused by steroid medications (iatrogenic). Consequently, most patients are effectively treated by carefully tapering off (and eventually stopping) the medication that causes the symptoms. If an adrenal adenoma is identified it may be removed by surgery. An ACTH-secreting corticotrophic pituitary adenoma should be removed after diagnosis. Regardless of the adenoma's location, most patients will require steroid replacement postoperatively at least in the interim as long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. Clearly, if both adrenals are removed, replacement with hydrocortisone or prednisolone is imperative. In those patients not suitable for or unwilling to undergo surgery, several drugs have been found to inhibit cortisol synthesis (e.g. ketoconazole, metyrapone) but they are of limited efficacy. Removal of the adrenals in the absence of a known tumor is occasionally performed to eliminate the production of excess cortisol. In some occasions, this removes negative feedback from a previously occult pituitary adenoma, which starts growing rapidly and produces extreme levels of ACTH, leading to hyperpigmentation. This clinical situation is known as Nelson's syndrome.[5]

[edit] Epidemiology Iatrogenic Cushing's (caused by treatment with corticosteroids) is the most common form of Cushing's syndrome. The incidence of pituitary tumors may be relatively high, as much as one in five people, [6] but only a minute fraction are active and produce excessive hormones.

[edit] Hyperadrenocorticism in domestic animals

Hyperadrenocorticism is an uncommon disease in pets, though of the endocrinopathies that do occur it is amongst the most common. In dogs, it is the second most common endocrinopathy behind hypothyroidism, though the disease is somewhat rare in cats. Roughly 85% are caused by pituitary-dependent causes, with the majority of these being due to functional pituitary neoplasms. Adrenal-dependent hyperadrenocorticism is rarer, and may derive from hyperplasia or neoplasia of the adrenal cortex. Hyperadrenocorticism in companion animals is usually treated with long term drug therapy. In dogs, treatment is accomplished with trilostane or with mitotane.[7] Dogs with pituitary-dependent Cushing's syndrome may be treated by radiation therapy directed against a pituitary adenoma. Productive adrenal tumors in dogs may be treated by nonurgent adrenalectomy. Adrenalectomy has been used as a treatment of pituitary-dependent cases, where the pituitary is not amenable to surgery. Ketaconazole has an off-target antisteroidogenic property which has been used to stabilise Cushing's dogs, and about a 50% response to treatment is seen in these patients. Selegiline, a monoamine oxidase inhibitor used in humans as an antidepressant, has also been successfully used to stabilise hyperadrenocorticism prior to surgery. The drug enhances dopaminergic inhibitory feedback on the hypothalamic-pituitary axis, reducing release of ACTH and thus corticosteroid production. In Equine Cushing's Syndrome, surgical treatment is impractical, and the drugs pergolide and cyproheptadine are indicated. Pergolide has been called the "treatment of choice" and improves more signs and symptoms than cyproheptadine in most studies.[8] It produces very few side effects.[9] However, cyproheptadine is still effective in some horses and is less expensive.[10]

Hypovolemia From Wikipedia, the free encyclopedia

Jump to: navigation, search Hypovolemia Classification and external resources

ICD-10 E86., R57.1, T81.1 ICD-9

276.52

MeSH

D020896

In physiology and medicine, hypovolemia (also hypovolaemia) is a state of decreased blood volume; more specifically, decrease in volume of blood plasma. Volumetric thirst can be caused by a number of things including bleeding and diarrhea.

Contents [hide]

• • •

1 Causes 2 Bodily response o 2.1 Acute response o 2.2 Kidney o 2.3 Heart o 2.4 Thirst o 2.5 Other response 3 Diagnosis 4 Treatment o 4.1 First aid o 4.2 Field care o 4.3 Hospital treatment 5 History 6 References 7 See also

•

8 External links

• •

• •

[edit] Causes Common causes of hypovolemia can be dehydration, bleeding, vomiting[1], severe burns and drugs such as diuretics or vasodilators typically used to treat hypertensive individuals. Rarely, it may occur as a result of a blood donation[2], sweating[1], and alcohol consumption[1].

[edit] Bodily response To respond to hypovolemia is a task for the body fluid balance systems as well as osmotic balance systems. Following an acute response, this function is accomplished by two sets of receptors; one in the kidneys and the other in the heart. [edit] Acute response Further information: Baroreflex The first response to hypovolemia is an inversed baroreflex, where a lack of activation of baroreceptors results in elevation of total peripheral resistance and cardiac output via

increased contractility of the heart, heart rate, and arterial vasoconstriction,[3]which tends to increase blood pressure. [edit] Kidney Main article: Renin-angiotensin system The kidneys have a specialized set of cells called Granular Cells that enable the recognition of changes in blood flow to the kidneys.[1] Naturally, these cells detect the presence of hypovolemia and react accordingly to the loss of blood volume. These cells secrete a hormone called renin when there is a decrease in the flow of blood to the kidneys.[1] Renin flows into the blood and there, initiates the conversion of a protein called angiotensinogen to angiotensin.[1] In order to exert its effects on the body, angiotensin I must be converted by enzymes into its active form, angiotensin II. Physiologically, angiotensin II stimulates the release of hormones by the posterior pituitary gland (ADH, also known as vasopressin) and the adrenal cortex (aldosterone). Aldosterone causes the kidneys to reabsorb sodium, leading to the reabsorption of water. ADH (vasopressin) also causes the kidneys to reabsorb water. Angiotensin II increases blood pressure by contracting arterial muscles. [edit] Heart Further reading:Atrial natriuretic peptide The next set of receptors responsible for detecting volumetric insufficiency are located in the heart atria. Commonly referred to as stretch receptors, these atrial baroreceptors detect the amount of blood that is being pumped back into the heart from the veins.[1] The body constantly returns blood to the heart through veins. Therefore, when the volume of blood being transported back to the heart is decreased, these receptors detect the change in the amount of blood thereby reducing the release of atrial natriuretic peptide. [edit] Thirst Main article: Extracellular thirst Both the activation of the renin angiotensin system and the decrease in atrial natriuretic peptide, along with their other functions, contribute to elicit thirst, by affecting the subfornical organ.[4]

[edit] Other response Furthermore, as intravascular fluid decreases, blood pressure is reduced and some compensation occurs as fluid from other cellular compartments moves into the vasculature. Fluid is passively transferred from all of the fluid compartments in the body, including intracellular, interstitial and other extravascular compartments.[1]

[edit] Diagnosis Clinical symptoms may not be present until 10-20% of total whole-blood volume is lost. Hypovolemia can be recognized by elevated pulse, diminished blood pressure, and the absence of perfusion as assessed by skin signs (skin turning pale) and/or capillary refill on forehead, lips and nail beds. The patient may feel dizzy, faint, nauseated, or very thirsty. These signs are also characteristic of most types of shock. Note that in children, compensation can result in an artificially high blood pressure despite hypovolemia. This is another reason (aside from initial lower blood volume) that even the possibility of internal bleeding in children should always be treated aggressively. Also look for obvious signs of external bleeding while remembering that people can bleed to death internally without any external blood loss. Also consider possible mechanisms of injury (especially the steering wheel and/or use/non-use of seat belt in motor vehicle accidents) that may have caused internal bleeding such as ruptured or bruised internal organs. If trained to do so and the situation permits, conduct a secondary survey and check the chest and abdominal cavities for pain, deformity, guarding or swelling. (Injuries to the pelvis and bleeding into the thigh from the femoral artery can also be life-threatening.)

[edit] Treatment Minor hypovolemia from a known cause that has been completely controlled (such as a blood donation from a healthy patient who is not anemic) may be countered with initial rest for up to half an hour. Oral fluids including moderate sugars (apple juice is good) and rich in electrolytes are needed to replenish the organism of lost sodium ions. Furthermore the advice is to the donor to eat good solid meals with proteins for the next few days. Typically, this would involve a fluid volume of less than one liter (1000 ml), although this is highly dependent on body weight. Larger people can tolerate slightly more blood loss than smaller people. More serious hypovolemia should be assessed by a nurse or doctor. When in doubt, treat hypovolemia aggressively.

[edit] First aid External bleeding should be controlled by direct pressure. If direct pressure fails, other techniques such as elevation and pressure points should be considered. The tourniquet should be used in the case of massive hemorrhage i.e. arterial bleeds, such as the femoral artery, as a last resort, for the use of a tourniquet can kill all the tissue below its application upon a limb, making amputation necessary. If a first-aider recognizes internal bleeding, the life-saving measure to take is to immediately call for emergency assistance.

[edit] Field care Emergency oxygen should be immediately employed to increase the efficiency of the patient's remaining blood supply. This intervention can be life-saving. The use of intravenous fluids (IVs) may help compensate for lost fluid volume, but IV fluids cannot carry oxygen in the way that blood can. See also emergency medical services for a discussion of techniques used in IV fluid management of hypovolemia.

[edit] Hospital treatment If the hypovolemia was caused by medication, the administration of antidotes may be appropriate but should be carefully monitored to avoid shock or the emergence of other pre-existing conditions. Blood transfusions coupled with surgical repair are the definitive treatment for hypovolemia caused by trauma. See also the discussion of shock and the importance of treating reversible shock while it can still be countered.

[edit] History Hypovolemia has historically been termed desanguination (from Latin sanguis, blood), meaning a massive loss of blood. The term was widely used by the Hippocrates in traditional medicine practiced in the Greco-Roman civilization and in Europe during the Middle Ages. The word was possibly used to describe the lack of personality (by death or by weakness) that often occurred once a person suffered hemorrhage or massive blood loss.

Hypervolemia From Wikipedia, the free encyclopedia

Jump to: navigation, search Hypervolemia Classification and external resources

ICD-10

E87.7

ICD-9

276.6

Hypervolemia, or fluid overload, is the medical condition where there is too much fluid in the blood.

The opposite condition is Hypovolemia (too little fluid volume in the blood).

Contents [hide] • • •

1 Pathophysiology 2 Causes 3 See also

•

4 External links

[edit] Pathophysiology This fluid, primarily salt and water, builds up in various locations in the body and leads to an increase in weight, swelling in the legs and arms (peripheral edema), and/or fluid in the abdomen (ascites). Eventually, the fluid enters the air spaces in the lungs, reduces the amount of oxygen that can enter the blood, and causes shortness of breath (dyspnea). Fluid can also collect in the lungs when lying down at night and can make nighttime breathing and sleeping difficult (Paroxysmal nocturnal dyspnea).

[edit] Causes Fluid overload can be caused by many reasons, including problems with the heart, kidneys, or lungs or a combination of any of these vital organs. Fluid overload can also be experienced after certain surgical operations. Congestive Heart Failure is the most common result of fluid overload.

Coeliac disease From Wikipedia, the free encyclopedia

Jump to: navigation, search Coeliac disease Classification and external resources

Biopsy of small bowel showing coeliac disease manifested by blunting of villi, crypt hyperplasia, and lymphocyte infiltration of crypts.

ICD-10

K90.0

ICD-9

579.0

OMIM

212750

DiseasesDB 2922 MedlinePlus 000233 med/308 eMedicine ped/2146 radio/652 MeSH

D002446

Coeliac disease (pronounced /ˈsiːli.æk/), also spelled celiac disease, is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy. Symptoms include chronic diarrhoea, failure to thrive (in children), and fatigue, but these may be absent and symptoms in all other organ systems have been described. It is estimated to affect about 1% of all Indo-European populations, but is thought to be significantly underdiagnosed. A growing portion of diagnoses are being made in asymptomatic persons as a result of increased screening.[1] Coeliac disease is caused by a reaction to gliadin, a gluten protein found in wheat (and similar proteins of the tribe Triticeae which includes other cultivars such as barley and rye). Upon exposure to gliadin, the enzyme tissue transglutaminase modifies the protein, and the immune system cross-reacts with the bowel tissue, causing an inflammatory

reaction. That leads to flattening of the lining of the small intestine (called villous atrophy). This interferes with the absorption of nutrients because the intestinal villi are responsible for absorption. The only effective treatment is a lifelong gluten-free diet. While the disease is caused by a reaction to wheat proteins, it is not the same as wheat allergy. This condition has several other names, including: cœliac disease (with "œ" ligature), c(o)eliac sprue, non-tropical sprue, endemic sprue, gluten enteropathy or glutensensitive enteropathy, and gluten intolerance. The term coeliac derives from the Greek κοιλιακός (koiliakόs, abdominal), and was introduced in the 19th century in a translation of what is generally regarded as an ancient Greek description of the disease by Aretaeus of Cappadocia.[2]

Contents [hide] •

•

•

•

• • •

1 Signs and symptoms o 1.1 Gastrointestinal o 1.2 Malabsorption-related o 1.3 Miscellaneous o 1.4 Other grains 2 Diagnosis o 2.1 Blood tests  2.1.1 Antibody testing  2.1.2 HLA genetic typing o 2.2 Endoscopy o 2.3 Pathology o 2.4 Other diagnostic tests 3 Pathophysiology o 3.1 Genetics o 3.2 Prolamins o 3.3 Tissue transglutaminase o 3.4 Villous atrophy and malabsorption o 3.5 Risk modifiers 4 Treatment o 4.1 Diet o 4.2 Refractory disease o 4.3 Experimental treatments 5 Screening and case finding 6 Epidemiology 7 Social and religious issues o 7.1 Christian churches & the Eucharist o 7.2 Roman Catholic position o 7.3 Coeliacs and Passover

• •

8 History 9 References

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10 External links

[edit] Signs and symptoms v d

This article is part of the Gluten sensitivity series. Coeliac disease Wheat allergy GS idiopathic neuropathies Dermatitis herpetiformis Oat sensitivity Gluten immunochemistry Gluten-free diet GSE associated conditions Anti-gliadin antibodies Anti-transglutaminase antibodies HLA-DQ2, HLA-DQ8

Classic symptoms of coeliac disease include diarrhea, weight loss (or stunted growth in children), and fatigue, but while coeliac disease is primarily a bowel disease, bowel symptoms may also be limited or even absent. Some patients are diagnosed with symptoms related to the decreased absorption of nutrients or with various symptoms which, although statistically linked, have no clear relationship with the malfunctioning bowel. Given this wide range of possible symptoms, the classic triad is no longer a requirement for diagnosis. Children between 9 and 24 months tend to present with bowel symptoms and growth problems shortly after first exposure to gluten-containing products. Older children may have more malabsorption-related problems and psychosocial problems, while adults generally have malabsorptive problems.[3] Many adults with subtle disease only have fatigue or anaemia.[1]

[edit] Gastrointestinal The diarrhoea characteristic of coeliac disease is pale, voluminous and malodorous. Abdominal pain and cramping, bloatedness with abdominal distention (thought to be due to fermentative production of bowel gas) and mouth ulcers[4] may be present. As the bowel becomes more damaged, a degree of lactose intolerance may develop. However, the variety of gastrointestinal symptoms that may be present in patients with coeliac disease is great, and some may have a normal bowel habit or even tend towards

constipation. Frequently the symptoms are ascribed to irritable bowel syndrome (IBS), only later to be recognised as coeliac disease; a small proportion of patients with symptoms of IBS have underlying coeliac disease, and screening may be justified.[5] Coeliac disease leads to an increased risk of both adenocarcinoma and lymphoma of the small bowel, which returns to baseline with diet. Longstanding disease may lead to other complications, such as ulcerative jejunitis (ulcer formation of the small bowel) and stricturing (narrowing as a result of scarring).[6]

[edit] Malabsorption-related The changes in the bowel make it less able to absorb nutrients, minerals and the fatsoluble vitamins A, D, E, and K.[3] • •

•

• •

The inability to absorb carbohydrates and fats may cause weight loss (or failure to thrive/stunted growth in children) and fatigue or lack of energy. Anaemia may develop in several ways: iron malabsorption may cause iron deficiency anaemia, and folic acid and vitamin B12 malabsorption may give rise to megaloblastic anaemia. Calcium and vitamin D malabsorption (and compensatory secondary hyperparathyroidism) may cause osteopenia (decreased mineral content of the bone) or osteoporosis (bone weakening and risk of fragility fractures). A small proportion (10%) have abnormal coagulation due to deficiency of vitamin K, and are slightly at risk for abnormal bleeding. Coeliac disease is also associated with bacterial overgrowth of the small intestine, which can worsen malabsorption, or cause malabsorption after treatment.[7]

[edit] Miscellaneous Coeliac disease has been linked with a number of conditions. In many cases it is unclear whether the gluten-induced bowel disease is a causative factor or whether these conditions share a common predisposition. •

•

•

IgA deficiency is present in 2% of patients with coeliac disease, and in turn this condition features a tenfold increased risk of coeliac disease.[8][9] Other features of this condition are an increased risk of infections and autoimmune disease. Dermatitis herpetiformis; this itchy cutaneous condition has been linked to a transglutaminase enzyme in the skin, features small bowel changes identical to those in coeliac disease[10] and occurs more often (in 2%) in patients with coeliac disease.[3] Neurological associations: epilepsy, ataxia (coordination problems), myelopathy, peripheral neuropathy, and schizophrenia [11] have all been linked with coeliac disease, but the strength of these associations and the causality are still subject to debate.[12]

•

• •

•

Growth failure and/or pubertal delay in later childhood can occur even without obvious bowel symptoms or severe malnutrition. Evaluation of growth failure often includes coeliac screening. Miscarriage and infertility. Hyposplenism (a small and underactive spleen) - it is unclear whether this actually increases infection risk in the same way as in other people without a functioning spleen.[13] Other auto-immune disorders: diabetes mellitus type 1,[14] autoimmune thyroiditis,[15] primary biliary cirrhosis,[16] and microscopic colitis.[17]

[edit] Other grains Wheat varieties or subspecies containing gluten and related species such as barley and rye also induce symptoms of coeliac disease.[18] A small minority of coeliac patients also react to oats.[19][20] It is most probable that oats produce symptoms due to cross contamination with other grains in the fields or in the distribution channels.[3] Generally, oats are therefore not recommended[18], though gluten-free oats are available in some locales and may be tried with caution.[21] Other cereals, such as maize (corn), quinoa, millet, sorghum, chia seed, and rice are safe for patients to consume. Non-cereal carbohydrate-rich foods such as potatoes and bananas do not contain gluten and do not trigger symptoms.

[edit] Diagnosis There are several tests that can be used to assist in diagnosis. The level of symptoms may determine the order of the tests, but all tests lose their usefulness if the patient is already taking a gluten-free diet. Intestinal damage begins to heal within weeks of gluten being removed from the diet, and antibody levels decline over months. For those who have already started on a gluten-free diet, it may be necessary to perform a re-challenge with 10 g of gluten (four slices of bread) per day over 2–6 weeks before repeating the investigations. Those who experience severe symptoms (e.g. diarrhoea) earlier can be regarded as sufficiently challenged and can be tested earlier.[3] Combining findings into a prediction rule to guide use of endoscopy reported a sensitivity of 100% (it would identify all the cases) and specificity of 61% (it would be incorrectly positive in 39%). The prediction rule recommends that patients with high risk symptoms or positive serology should undergo endoscopy. The study defined high risk symptoms as weight loss, anaemia (haemoglobin less than 120 g/l in females and less than 130 g/l in males), or diarrhoea (more than three loose stools per day).[22]

[edit] Blood tests [edit] Antibody testing

Serological blood tests are the first-line investigation required to make a diagnosis of coeliac disease. Serology for anti-tTG antibodies has superseded older serological tests and has a high sensitivity (99%) and specificity (>90%) for identifying coeliac disease. Modern anti-tTG assays rely on a human recombinant protein as an antigen.[23] Because of the major implications of a diagnosis of coeliac disease, professional guidelines recommend that a positive blood test is still followed by an endoscopy/gastroscopy and biopsy. A negative serology test may still be followed by a recommendation for endoscopy and duodenal biopsy if clinical suspicion remains high due to the 1 in 100 "false-negative" result. As such tissue biopsy is still considered the gold standard in the diagnosis of coeliac disease.[3][6] Historically three other antibodies were measured: anti-reticulin (ARA), anti-gliadin (AGA) and anti-endomysium (EMA) antibodies. Serology may be unreliable in young children, with anti-gliadin performing somewhat better than other tests in children under five.[24] Serology tests are based on indirect immunofluorescence (reticulin, gliadin and endomysium) or ELISA (gliadin or tissue transglutaminase).[25] Guidelines recommend that a total serum IgA Blood HLA tests for coeliac disease[27] level is checked in parallel, as coeliac patients with IgA deficiency may be unable to produce the antibodies on which these tests depend ("false Test sensitivity specificity negative"). In those patients, IgG antibodies against transglutaminase (IgG-TTG) may be diagnostic.[26] HLA-DQ2 94% 73% [edit] HLA genetic typing Antibody testing and HLA testing have similar accuracies.[27]

HLA-DQ8

12%

81%

[edit] Endoscopy

Endoscopic still of duodenum of patient with coeliac disease showing scalloping of folds.

Schematic of the Marsh classification of upper jejunal pathology in coeliac disease An upper endoscopy with biopsy of the duodenum (beyond the duodenal bulb) or jejunum is performed. It is important for the physician to obtain multiple samples (four to eight) from the duodenum. Not all areas may be equally affected; if biopsies are taken from healthy bowel tissue, the result would be a false negative.[6] Most patients with coeliac disease have a small bowel that appears normal on endoscopy; however, five concurrent endoscopic findings have been associated with a high specificity for coeliac disease: scalloping of the small bowel folds (pictured), paucity in the folds, a mosaic pattern to the mucosa (described as a cracked-mud appearance), prominence of the submucosa blood vessels, and a nodular pattern to the mucosa.[28] Until the 1970s, biopsies were obtained using metal capsules attached to a suction device. The capsule was swallowed and allowed to pass into the small intestine. After x-ray verification of its position, suction was applied to collect part of the intestinal wall inside the capsule. One often-utilised capsule system is the Watson capsule. This method has now been largely replaced by fibre-optic endoscopy, which carries a higher sensitivity and a lower frequency of errors.[29]

[edit] Pathology The classic pathology changes of coeliac disease in the small bowel are categorized by the "Marsh classification":[30] • • • • •

Marsh stage 0: normal mucosa Marsh stage 1: increased number of intra-epithelial lymphocytes, usually exceeding 20 per 100 enterocytes Marsh stage 2: proliferation of the crypts of Lieberkuhn Marsh stage 3: partial or complete villous atrophy Marsh stage 4: hypoplasia of the small bowel architecture

The changes classically improve or reverse after gluten is removed from the diet, so many official guidelines recommend a repeat biopsy several (4–6) months after commencement of gluten exclusion.[3] In some cases a deliberate gluten challenge, followed by biopsy, may be conducted to confirm or refute the diagnosis. A normal biopsy and normal serology after challenge indicates the diagnosis may have been incorrect.[3] Patients are warned that one does not "outgrow" coeliac disease in the same way as childhood food intolerances.

[edit] Other diagnostic tests

Other tests that may assist in the diagnosis are blood tests for a full blood count, electrolytes, calcium, renal function, liver enzymes, vitamin B12 and folic acid levels. Coagulation testing (prothrombin time and partial thromboplastin time) may be useful to identify deficiency of vitamin K, which predisposes patients to hemorrhage. These tests should be repeated on follow-up, as well as anti-tTG titres.[3] Some professional guidelines[3] recommend screening of all patients for osteoporosis by DXA/DEXA scanning.

[edit] Pathophysiology Coeliac disease appears to be polyfactorial, both in that more than one genetic factor can cause the disease and also more than one factor is necessary for the disease to manifest in a patient. Almost all coeliac patients have the variant HLA DQ2 allele.[1] However, about 20–30% of people without coeliac disease have inherited an HLA-DQ2 allele.[27] This suggests additional factors are needed for coeliac disease to develop. Furthermore, about 5% of those people who do develop coeliac disease do not have the DQ2 gene.[1] The HLA-DQ2 allele shows incomplete penetrance, as the gene alleles associated with the disease appear in most patients, but are neither present in all cases nor sufficient by themselves to cause the disease.

[edit] Genetics The vast majority of coeliac patients have one of two types of HLA DQ.[27] This gene is part of the MHC class II antigen-presenting receptor (also called the human leukocyte antigen) system and distinguishes cells between self and non-self for the purposes of the immune system. There are 7 HLA DQ variants (DQ2 and DQ4 through 9). Two of these variants—DQ2 and DQ8—are associated with coeliac disease. The gene is located on the short arm of the sixth chromosome, and as a result of the linkage this locus has been labeled CELIAC1.

DQ α5-β2 -binding cleft with a deamidated gliadin peptide (yellow), modified from PDB 1S9V[31]

Over 95% of coeliac patients have an isoform of DQ2 (encoded by DQA1*05 and DQB1*02 genes) and DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), which is inherited in families. The reason these genes produce an increase in risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate T lymphocytes and initiate the autoimmune process.[1] Most coeliac patients bear a two-gene HLA-DQ haplotype referred to as DQ2.5 haplotype. This haplotype is composed of 2 adjacent gene alleles, DQA1*0501 and DQB1*0201, which encode the two subunits, DQ α5 and DQ β2. In most individuals, this DQ2.5 isoform is encoded by one of two chromosomes 6 inherited from parents. Most coeliacs inherit only one copy of this DQ2.5 haplotype, while some inherit it from both parents; the latter are especially at risk for coeliac disease, as well as being more susceptible to severe complications.[32] Some individuals inherit DQ2.5 from one parent and portions of the haplotype (DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent, called a trans-haplotype association, and these individuals are at similar risk for coeliac disease as those with a single DQ2.5 bearing chromosome 6, but in this instance disease tends not to be familial. Among the 6% of European coeliacs that do not have DQ2.5(cis or trans) or DQ8, 4% have the DQ2.2 isoform and the remaining 2% lack DQ2 or DQ8.[33] The frequency of these genes varies geographically. DQ2.5 has high frequency in peoples of North and Western Europe (Basque Country, Ireland,[34] with highest frequencies), portions of Africa, and is associated with disease in India,[35] but is not found along portions of the West Pacific rim. DQ8, spread more globally than DQ2.5, is more prevalent from South and Central America (up to 90% phenotype frequency).[36]

[edit] Prolamins The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolamins. These are storage proteins rich in proline (prol-) and glutamine (-amin) that dissolve in alcohols and are resistant to proteases and peptidases of the gut.[37][1] One region of α-gliadin stimulates membrane cells, enterocytes, of the intestine to allow larger molecules around the sealant between cells. Disruption of tight junctions allow peptides larger than 3 amino acids to enter circulation.[38]

Illustration of deamidated α-2 gliadin's 33mer, amino acids 56-88, showing the overlapping of 3 varieties of T-cell epitope.[39] Membrane leaking permits peptides of gliadin that stimulate two levels of immune response, the innate response and the adaptive (T-helper cell mediated) response. One protease resistant peptide from α-gliadin contains a region that stimulates lymphocytes and results in the release of interleukin-15. This innate response to gliadin results in

immune system signaling that attracts inflammatory cells and increases the release inflammatory chemicals.[1] The strongest and most common adaptive response to gliadin is directed toward a α2-gliadin fragment of 33 amino acids in length.[1] The response to 33mer occurs in most coeliacs who have a DQ2 isoform. This peptide, when altered by intestinal transglutaminase, has a high density of overlapping T-cell epitopes. This increases the likelihood that the DQ2 isoform will bind and stay bound to peptide when recognized by T-cells.[39] Gliadin in wheat is the best-understood member of this family, but other prolamins exist and hordein (from barley), and secalin (from rye) may contribute to coeliac disease.[1][40] However, not all prolamins will cause this immune reaction and there is ongoing controversy on the ability of avenin (the prolamin found in oats) to induce this response in coeliac disease.

[edit] Tissue transglutaminase

Tissue transglutaminase, drawn from PDB 1FAU. Anti-transglutaminase antibodies to the enzyme tissue transglutaminase (tTG) are found in an overwhelming majority of cases.[41] Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively.[1] Stored biopsies from suspected coeliac patients has revealed that autoantibody deposits in the subclinical coeliacs are detected prior to clinical disease. These deposits are also found in patients who present with other autoimmune diseases, anemia or malabsorption phenomena at a much increased rate over the normal population.[42] Endomysial component of antibodies (EMA) to tTG are believed to be directed toward cell surface transglutaminase, and these antibodies are still used in confirming a coeliac disease diagnosis. However, a 2006 study showed that EMA-negative coeliac patients tend to be older males with more severe abdominal symptoms and a lower frequency of "atypical" symptoms including autoimmune disease.[43] In this study the anti-tTG antibody deposits did not correlate with the severity of villous destruction. These findings, coupled with recent work showing that gliadin has an innate response component,[44] suggests that gliadin may be more responsible for the primary manifestations of coeliac disease whereas tTG is a bigger factor in secondary effects such as allergic responses and secondary autoimmune diseases. In a large percentage of coeliac patients the anti-tTG antibodies also recognize a rotavirus protein called VP7. These antibodies stimulate monocytes proliferation and rotavirus infection might explain some early steps in the cascade of immune cell proliferation.[45] Indeed, earlier studies of rotavirus damage in the gut showed this causes a villous atrophy.[46] This suggests that viral proteins may take part in the initial flattening and stimulate self-crossreactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin mediated tTG presentation provides a second source of crossreactive antibodies.

[edit] Villous atrophy and malabsorption

The inflammatory process, mediated by T cells, leads to disruption of the structure and function of the small bowel's mucosal lining, and causes malabsorption as it impairs the body's ability to absorb nutrients, minerals and fat-soluble vitamins A, D, E and K from food. Lactose intolerance may be present due to the decreased bowel surface and reduced production of lactase but typically resolves once the condition is treated. Alternative causes of this tissue damage have been proposed and involve release of interleukin 15 and activation of the innate immune system by a shorter gluten peptide (p31–43/49). This would trigger killing of enterocytes by lymphocytes in the epithelium.[1] The villous atrophy seen on biopsy may also be due to unrelated causes, such as tropical sprue, giardiasis and radiation enteritis. While positive serology and typical biopsy are highly suggestive of coeliac disease, lack of response to diet may require these alternative diagnoses to be considered.[6]

[edit] Risk modifiers There are various theories as to what determines whether a genetically susceptible individual will go on to develop coeliac disease. Major theories include infection by rotavirus[47] or human intestinal adenovirus.[48] Some research has suggested that smoking is protective against adult onset coeliac disease.[49] A 2005 prospective and observational study found that timing of the exposure to gluten in childhood was an important risk modifier. People exposed to wheat, barley, or rye before the gut barrier has fully developed (three months after birth) had five times the risk of developing coeliac disease over those exposed at 4 to 6 months. Those exposed later had a slightly increased risk relative to those exposed at 4 to 6 months.[50] However a 2006 study with similar numbers found just the reverse, that early introduction of grains was protective.[51] Breastfeeding may also reduce risk. A meta-analysis indicates that prolonging breastfeeding until the introduction of gluten-containing grains into the diet was associated with a 52% reduced risk of developing coeliac disease in infancy; whether this persists into adulthood is not clear.[52]

[edit] Treatment [edit] Diet Main article: Gluten-free diet Presently, the only effective treatment is a life-long gluten-free diet.[18] No medication exists that will prevent damage, or prevent the body from attacking the gut when gluten is present. Strict adherence to the diet allows the intestines to heal, leading to resolution of all symptoms in most cases and, depending on how soon the diet is begun, can also eliminate the heightened risk of osteoporosis and intestinal cancer.[53] Dietician input is generally requested to ensure the patient is aware which foods contain gluten, which foods are safe, and how to have a balanced diet despite the limitations. In many countries gluten-free products are available on prescription and may be reimbursed by health

insurance plans. More manufacturers are producing gluten-free products, some of which are almost indistinguishable from their gluten-containing counterparts. The diet can be cumbersome; failure to comply with the diet may cause relapse. The term "gluten-free" is generally used to indicate a supposed harmless level of gluten rather than a complete absence.[54] The exact level at which gluten is harmless is uncertain and controversial. A recent systematic review tentatively concluded that consumption of less than 10 mg of gluten per day is unlikely to cause histological abnormalities, although it noted that few reliable studies had been done.[54] Regulation of the label "gluten-free" varies widely by country. For example, in the United States the term "gluten-free" is not yet regulated.[55] The current international Codex Alimentarius standard, established in 1981, allows for 50 mg N/100 g on dry matter,[56] although a proposal for a revised standard of 20 ppm in naturally gluten-free products and 200 ppm in products rendered gluten-free has been accepted.[57] Gluten-free products are usually more expensive and harder to find than common gluten-containing foods.[58] Since ready-made products often contain traces of gluten, some coeliacs may find it necessary to cook from scratch.[57] Even while on a diet, health-related quality of life (HRQOL) may be lower in people with coeliac disease. Studies in the United States have found that quality of life becomes comparable to the general population after staying on the diet while studies in Europe have found that quality of life remains lower, although the surveys are not quite the same.[59] Men tend to report more improvement than women.[60] Some have persisting digestive symptoms or dermatitis herpetiformis, mouth ulcers, osteoporosis and resultant fractures. Symptoms suggestive of irritable bowel syndrome may be present, and there is an increased rate of anxiety, fatigue, dyspepsia and musculoskeletal pain.[61]

[edit] Refractory disease A tiny minority of patients suffer from refractory disease, which means they do not improve on a gluten-free diet. This may be because the disease has been present for so long that the intestines are no longer able to heal on diet alone, or because the patient is not adhering to the diet, or because the patient is consuming foods that are inadvertently contaminated with gluten. If alternative causes have been eliminated, steroids or immunosuppressants (such as azathioprine) may be considered in this scenario.[6]

[edit] Experimental treatments Various other approaches are being studied that would reduce the need of dieting. All are still under development, and are not expected to be available to the general public for a while:[1] •

•

Genetically engineered wheat species, or wheat species that have been selectively bred to be minimally immunogenic. This, however, could interfere with the effects that gliadin has on the quality of dough. A combination of enzymes (prolyl endopeptidase and a barley glutamine-specific cysteine endopeptidase (EP-B2)) that degrade the putative 33-mer peptide in the

•

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duodenum. This combination would enable coeliac disease patients to consume gluten-containing products.[62] Inhibition of zonulin, an endogenous signaling protein linked to increased permeability of the bowel wall and hence increased presentation of gliadin to the immune system.[63] Other treatments aimed at other well-understood steps in the pathogenesis of coeliac disease, such as the action of HLA-DQ2 or tissue transglutaminase and the MICA/NKG2D interaction that may be involved in the killing of enterocytes (bowel lining cells).

[edit] Screening and case finding There is significant debate as to the benefits of screening. Some studies suggest that early detection would decrease the risk of osteoporosis and anaemia. In contrast, a cohort studied in Cambridge suggested that people with undetected coeliac disease had a beneficial risk profile for cardiovascular disease (less overweight, lower cholesterol levels).[1] Due to its high sensitivity, serology has been proposed as a screening measure, because the presence of antibodies would detect previously undiagnosed cases of coeliac disease and prevent its complications in those patients. Serology may also be used to monitor adherence to diet: in those who still ingest gluten, antibody levels remain elevated.[3][6] In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) recommends screening for coeliac disease in patients with newly diagnosed chronic fatigue syndrome[64] and irritable bowel syndrome.[65] Other clinical scenarios in which screening may be justified include type 1 diabetes,[14] unexplained iron-deficiency anemia,[66][67] Down's syndrome, Turner's syndrome, lupus, and autoimmune thyroid disease.[68]

[edit] Epidemiology The prevalence of clinically diagnosed disease (symptoms prompting diagnostic testing) is 0.05–0.27% in various studies. However, population studies from parts of Europe, India, South America, Australasia and the USA (using serology and biopsy) indicate that the prevalence may be between 0.33 and 1.06% in children (5.66% in one study of Saharawi children[69]) and 0.18–1.2% in adults.[1] People of African, Japanese and Chinese descent are rarely diagnosed; this reflects a much lower prevalence of the genetic risk factors. Population studies also indicate that a large proportion of coeliacs remain undiagnosed; this is due to many clinicians being unfamiliar with the condition.[70] A large multicentre study in the U.S. found a prevalence of 0.75% in not-at-risk groups, rising to 1.8% in symptomatic patients, 2.6% in second-degree relatives of a patient with coeliac disease and 4.5% in first-degree relatives. This profile is similar to the prevalence

in Europe.[71] Other populations at increased risk for coeliac disease, with prevalence rates ranging from 5% to 10%, include individuals with Down and Turner syndromes, type 1 diabetes, and autoimmune thyroid disease, including both hyperthyroidism (overactive thyroid) and hypothyroidism (underactive thyroid).[72] Historically, coeliac disease was thought to be rare, with a prevalence of about 0.02%.[72] Recent increases in the number of reported cases may be due to changes in diagnostic practice.[73]

[edit] Social and religious issues [edit] Christian churches & the Eucharist Most mainline Christian churches offer their communicants gluten-free alternatives to the sacramental bread, usually in the form of a rice-based cracker or gluten-free bread. These include United Methodist, Christian Reformed, Episcopal, Lutheran, The Church of Jesus Christ of Latter-day Saints, and many others.[74]

[edit] Roman Catholic position Roman Catholic doctrine states that for a valid Eucharist the bread must be made from wheat. In 2002, the Congregation for the Doctrine of the Faith approved German-made low-gluten hosts, which meet all of the Catholic Church's requirements, for use in Italy; although not entirely gluten-free, they were also approved by the Italian Celiac Association.[75] Some Catholic coeliac sufferers have requested permission to use rice wafers; such petitions have always been denied.[76] The issue is more complex for priests. Though a Catholic (lay or ordained) receiving under either form is considered to have received Christ "whole and entire", the priest, who is acting in persona Christi, is required to receive under both species when offering Mass — not for the validity of his Communion, but for the fullness of the sacrifice of the Mass. On 22 August 1994, the Congregation for the Doctrine of the Faith apparently barred coeliacs from ordination, stating, "Given the centrality of the celebration of the Eucharist in the life of the priest, candidates for the priesthood who are affected by coeliac disease or suffer from alcoholism or similar conditions may not be admitted to holy orders." After considerable debate, the congregation softened the ruling on 24 July 2003 to "Given the centrality of the celebration of the Eucharist in the life of a priest, one must proceed with great caution before admitting to Holy Orders those candidates unable to ingest gluten or alcohol without serious harm."[77] As of January 2004, an extremely low-gluten host became available in the United States. The Benedictine Sisters of Perpetual Adoration in Clyde, MO, after ten years of work, have produced a low-gluten host safe for celiacs and also approved by the Catholic Church for use at Mass. Each host is made and packaged in a dedicated wheat-free / gluten-free environment. The hosts are made separately by hand, unlike the common host which is stamped out of a long thin sheet of bread by a cutter. Therefore, each host is a slightly different size and shape. Most importantly, the finished hosts have been analyzed

for gluten content. The gluten content of these hosts is reported as 0.01 %. In actuality, the gluten content is probably less than 0.01%. Sister Lynn, OSB, said that the result of the analysis of the finished host revealed "no gluten detected". The hosts are labeled as 0.01 % since the lowest limit of detection of this analysis was 0.01 %. In an article from the Catholic Review (15 February 2004) Dr. Alessio Fasano was quoted as declaring these hosts "perfectly safe for celiac sufferers." [78]

[edit] Coeliacs and Passover The Jewish festival of Pesach (Passover) may present problems with its obligation to eat matzo, which is unleavened bread made in a strictly controlled manner from wheat, barley, spelt, oats, or rye. This rules out many other grains that are normally used as substitutes for people with gluten sensitivity, especially for Ashkenazi Jews who also avoid rice. Many kosher for Passover products avoid grains altogether and are therefore gluten-free. Potato starch is the primary starch used to replace the grains. Consuming matzo is mandatory on the first night of Pesach only. Jewish law holds that a person should not seriously endanger one's health in order to fulfill a commandment. Thus, a person with severe coeliac disease is not required, or even allowed, to eat any matzo other than gluten-free matzo. The most commonly used gluten-free matzo is made from oats.