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The Territory government has announced its long awaited timeframe for banning smoking inside clubs and pubs, saying new restrictions will come into place from the start of 2010.

The ban will not include outdoor areas where food and drink is not directly served.

Minister Chris Burns says the ban will start in 2010 so businesses will have time to do building work or make other adjustments for the changes.

“Venues need time to carry out works on their rooms and venue to accommodate this change. That’s the advice that we’ve had from industry.

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http://www.abc.net.au/news/stories/2008/06/04/2264613.htm

Youth suicide dropping, but self harm on the rise

A young woman rests her head in her hands in a depressed pose

Experts say depression and anxiety can manifest themselves in self harm. (ABC News: Giulio Saggin)

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Australia has managed to reduce the number of teenage suicides but the latest figures from the Institute of Health and Welfare show there is a new problem that needs to be tackled, self harm.

In the past decade there has been an alarming rise in the number of young people who intentionally hurt themselves, with more than 7,000 taken to hospital in one year.

Youth suicide has long been recognised as a real and significant issue in Australian society.

But Professor George Patton from the Centre for Adolescent Health says more commonly, deep emotional pain can manifest itself as self harm.

“The act is not necessarily about killing yourself and for most young people self harm is not about killing yourself, it’s a way of dealing with emotions that you’re finding difficult,” he said.

“They may be emotions of feeling anxious, feeling angry, feeling unhappy, a mixture of all of the above.”

The latest figures from the Institute of Health and Welfare, released this morning, reveal the rate of self harm is rising dramatically.

In the decade from 1996 to 2006, the rate of hospitalisations from self-harm went up by 43 per cent among young people.

For young women, the increase was even higher at 51 per cent.

The institute’s Deanna Eldridge says that equates to 7,300 young people in the most recent statistical year.

“Overall it only accounts for about 2 per cent of all hospitalisations of young people, but in terms of injury it’s about the sixth leading cause of hospitalisation.

The Institute’s figures show about 80 per cent of the hospitalisations for self-harm were for deliberate poisoning.

Professor Patton says that is a reflection of the most serious cases but it is really only the tip of the iceberg and most cases of self-harm do not need immediate medical attention.

“The commonest type of self harm the young people report is deliberately cutting themselves,” he said.

“Self poisoning is the next most common and then things like deliberate risk taking, beating up on yourself or self battery – they’re less common again.”

Self harm is most common during puberty and reaches a peak at an average age of 15.

It is a problem all around the world and the rise of cases in Australia fits with similar trends in other Western countries.

Professor Patten says there is a growing feeling that the rise in self harm is actually a reflection of the growth of individualism and loss of connections.

“They are really important for young people as they’re growing up and so kids are growing up feeling that they actually need to deal with their problems themselves,” he said.

Youth depression groups, like Reach Out! have helped make progress in bringing down the suicide rate but spokesman Jonathan Nicholas thinks the figures show there is still a lot of work to do.

“We’ve made some good inroads into suicide but the journey is far from over and it says that we’ve actually got to do more in intervening early with young people and getting them to the supports they need and making sure that they are not reaching the point where they want to die,” he said.

Adapted from an AM report by youth affairs reporter Michael Turtle.

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http://www.abc.net.au/news/stories/2008/04/10/2212996.htm

Cough medicine prescriptions ‘an insult to parents’

Cough medicine for children under two will now be available by prescription only instead of over the counter in pharmacies.

Parents have expressed concern at the decision by the Government’s National Drug and Poisons Scheduling Committee.

The national president of the Pharmacy Guild, Kos Sclavos, says he believes the move is unnecessary.

“I guess we [would be] concerned if there was no consultation or supervision of these products, but that’s why pharmacists are there,” he said.

“They’re accessible, and they’re trained health professionals with university degrees.

“In the US and these other markets where these products have been withdrawn [it] is because you don’t get that advice [because the medicines are bought] from a supermarket aisle.

“So I think its an insult to many parents, based on the feedback pharmacists are giving me.”

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Link

Gov. Blagojevich announces statewide town hall meetings to address
IGNN (press release), IL – 14 hours ago
Together we can find solutions to underage drinking and help prevent the senseless tragedies associated with teen use.” According to IDHS statistics,
Meetings to target teen drinking Springfield State Journal Register
all 3 news articles »
Panel discusses underage drinking
Belleville News Democrat,  USA – 1 hour ago
The average age for first-time alcohol use in Madison County is 12, according to the 2006 Madison County Youth Survey. Panel member Megan Morse,
Town hall meeting tonight in Granite will address underage drinking Belleville News Democrat
all 3 news articles »
Town hall meeting about underage alcohol use
Emporia Gazette (subscription), KS – 13 hours ago
nationwide expected to hold town hall meetings in April in an attempt to change American attitudes and to raise awareness of underage alcohol use.
Town hall meeting focuses on underage drinking
The Daily Toreador (subscription), TX – 6 hours ago
“Most people think that when a student goes to college, it is kind of their right of passage to participate in alcohol use,” Britton-Stroud said.
Group to host panel on underage drinking
Anniston Star (subscription), AL – 3 hours ago
The meeting will feature a panel of experts from various walks of life, as well as videos and statistics about underage alcohol use in Calhoun County and
Parents Matter when it comes to underage drinking
Rapid City Journal, SD – 3 hours ago
The DVD said underage teenagers were 42 percent less likely to drink alcohol if they repeatedly heard a “no use” message. It also reported that, last year,
Underage Drinking Prevention Campaign KELOLAND TV
all 4 news articles »
Forum Helps Parents Address Underage Drinking
WCAV, VA – 6 hours ago
A community forum on underage drinking Monday night coincided with the start of Alcohol Awareness Month. Local health officials joined educators and
Underage drinking topic of Oldham meeting
Louisville Courier-Journal, KY – 11 hours ago
The meeting is designed to help raise awareness of the dangers of alcohol use and offer ways to prevent underage drinking. Police Chief Michael Griffin will
Underage drinking under the gun
Vicksburg Post, MS – 15 hours ago
They said they know some of the older kids drink beer and smoke, but said they wouldn’t feel shy about telling an older person drug and alcohol use is bad
Meeting focuses on teen drinking
UI The Daily Iowan (subscription), IA – 3 hours ago
MECCA plans to use input from the meeting in its application for the Sober Truth on Preventing Underage Drinking Act Grant, which provides money for

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http://www.emedicine.com/med/TOPIC3185.HTM

Definion

Hepatic encephalopathy is a syndrome observed in patients with cirrhosis. Hepatic encephalopathy is defined as a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction, after exclusion of other known brain disease. It is characterized by personality changes, intellectual impairment, and a depressed level of consciousness. An important prerequisite for the syndrome is diversion of portal blood into the systemic circulation through portosystemic collateral vessels. Indeed, hepatic encephalopathy may develop in patients without cirrhosis who have undergone portocaval shunt surgery. The development of hepatic encephalopathy is explained, to some extent, by the effect of neurotoxic substances, which occurs in the setting of cirrhosis and portal hypertension.

Subtle signs of hepatic encephalopathy are observed in nearly 70% of patients with cirrhosis. Symptoms may be debilitating in a significant number of patients and are observed in 24-53% of patients who undergo portosystemic shunt surgery. Approximately 30% of patients dying of end-stage liver disease experience significant encephalopathy, approaching coma.

Hepatic encephalopathy, accompanying the acute onset of severe hepatic synthetic dysfunction, is the hallmark of fulminant hepatic failure (FHF). Symptoms of encephalopathy in FHF are graded using the same scale used to assess encephalopathy symptoms in cirrhosis. The encephalopathy of cirrhosis and FHF share many of the same pathogenic mechanisms. However, brain edema plays a much more prominent role in FHF than in cirrhosis. The brain edema of FHF is attributed to increased permeability of the blood-brain barrier, impaired osmoregulation within the brain, and increased cerebral blood flow. The resulting brain cell swelling and brain edema are potentially fatal. In contrast, brain edema is rarely reported in patients with cirrhosis. The encephalopathy of FHF is not covered in this article but is addressed in Acute Liver Failure.

A recent conference proposed nomenclature for categorizing hepatic encephalopathy. Type A hepatic encephalopathy describes encephalopathy associated with acute liver failure. Type B hepatic encephalopathy describes encephalopathy associated with portal-systemic Bypass and no intrinsic hepatocellular disease. Type C hepatic encephalopathy describes encephalopathy associated with Cirrhosis and portal hypertension or portal-systemic shunts. Type C hepatic encephalopathy is, in turn, subcategorized as episodic, persistent, or minimal.

For excellent patient education resources, visit eMedicine’s Liver, Gallbladder, and Pancreas Center and Hepatitis Center. Also, see eMedicine’s patient education article Cirrhosis.

Pathogensis

A number of theories have been proposed to explain the development of hepatic encephalopathy in patients with cirrhosis. Some investigators contend that hepatic encephalopathy is a disorder of astrocyte function. Astrocytes account for about one third of cortical volume. They play a key role in the regulation of the blood-brain barrier. They are involved in maintaining electrolyte homeostasis and in providing nutrients and neurotransmitter precursors to neurons. They also play a role in the detoxification of a number of chemicals, including ammonia.

It is theorized that neurotoxic substances, including ammonia and manganese, may gain entry into the brain in the setting of liver failure. These neurotoxic substances may then contribute to morphologic changes in astrocytes. In cirrhosis, astrocytes may undergo Alzheimer type II astrocytosis. Here, astrocytes become swollen. They may develop a large pale nucleus, a prominent nucleolus, and margination of chromatin. In FHF, astrocytes may also become swollen. The changes of Alzheimer type II astrocytosis are not seen in FHF. But, in contrast to cirrhosis, astrocyte swelling in FHF may be so marked as to produce brain edema. This may lead to increased intracranial pressure and, potentially, brain herniation.

Previously, cerebral edema was not believed to be of clinical importance in the pathogenesis of hepatic encephalopathy in cirrhosis. However, increasing lines of evidence demonstrate that low-grade cerebral edema may exist in patients with cirrhosis and hepatic encephalopathy.

Recent work has focused on changes in gene expression in the brain. The gene coding for a wide array of transport proteins may be upregulated or downregulated in cirrhosis and FHF. As an example, the gene coding for the peripheral-type benzodiazepine receptor is upregulated in both cirrhosis and FHF. Such alterations in gene expression may ultimately result in impaired neurotransmission.

Hepatic encephalopathy may also be thought of as a disorder that is the end result of accumulated neurotoxic substances in the brain. Putative neurotoxins include short-chain fatty acids; mercaptans; false neurotransmitters, such as tyramine, octopamine, and beta-phenylethanolamines; manganese; ammonia; and gamma-aminobutyric acid (GABA).

Ammonia hypothesis

Ammonia is produced in the gastrointestinal tract by bacterial degradation of amines, amino acids, purines, and urea. Normally, ammonia is detoxified in the liver by conversion to urea by the Krebs-Henseleit cycle. Ammonia is also consumed in the conversion of glutamate to glutamine, a reaction that depends upon the activity of glutamine synthetase. Two factors contribute to the hyperammonemia that is seen in cirrhosis. First, there is a decreased mass of functioning hepatocytes, resulting in fewer opportunities for ammonia to be detoxified by the above processes. Secondly, portosystemic shunting may divert ammonia-containing blood away from the liver to the systemic circulation.

Normal skeletal muscle cells do not possess the enzymatic machinery of the urea cycle but do contain glutamine synthetase. Glutamine synthetase activity in muscle actually increases in the setting of cirrhosis and portosystemic shunting. Thus, skeletal muscle is an important site for ammonia metabolism in cirrhosis. However, the muscle wasting that is observed in patients with advanced cirrhosis may potentiate hyperammonemia.

The kidneys express glutaminase and, to some extent, play a role in ammonia production. However, the kidneys also express glutamine synthetase and play a key role in ammonia metabolism and excretion.

Brain astrocytes also possess glutamine synthetase. However, the brain is not able to increase glutamine synthetase activity in the setting of hyperammonemia. Thus, the brain remains vulnerable to the effects of hyperammonemia.

Ammonia has multiple neurotoxic effects. It can alter the transit of amino acids, water, and electrolytes across astrocytes and neurons. It can impair amino acid metabolism and energy utilization in the brain. Ammonia can also inhibit the generation of excitatory and inhibitory postsynaptic potentials.

Additional support for the ammonia hypothesis comes from the clinical observation that treatments that decrease blood ammonia levels can improve hepatic encephalopathy symptoms.

One argument against the ammonia hypothesis is the observation that approximately 10% of patients with significant encephalopathy have normal serum ammonia levels. Furthermore, many patients with cirrhosis have elevated ammonia levels without evidence for encephalopathy. Also, ammonia does not induce the classic electroencephalographic (EEG) changes associated with hepatic encephalopathy when it is administered to patients with cirrhosis.

GABA hypothesis

GABA is a neuroinhibitory substance produced in the gastrointestinal tract. Of all brain nerve endings, 24-45% may be GABAergic. For 20 years, it was postulated that hepatic encephalopathy was the result of increased GABAergic tone in the brain. However, recent experimental work is changing perceptions regarding the activity of the GABA receptor complex in cirrhosis.

The GABA receptor complex contains binding sites for GABA, benzodiazepines, and barbiturates. Until recently, it was believed that there were increased levels of GABA and endogenous benzodiazepines in plasma. These chemicals would then cross an extrapermeable blood-brain barrier. Binding of GABA and benzodiazepines to a supersensitive neuronal GABA receptor complex permitted the influx of chloride ions into the postsynaptic neuron, leading to generation of an inhibitory postsynaptic potential.

However, recent experimental work has demonstrated that there is no change in brain GABA or benzodiazepine levels. Similarly, there is no change in sensitivity of the receptors of the GABA receptor complex.

Previously, it was believed that administration of flumazenil, a benzodiazepine receptor antagonist, could improve mental function in patients with hepatic encephalopathy. It now appears that flumazenil improves mental function in only a small percentage of patients with cirrhosis.

The neuronal GABA receptor complex contains a binding site for neurosteroids. Today, some investigators contend that neurosteroids play a key role in hepatic encephalopathy.

In experimental models, neurotoxins, like ammonia and manganese, increase the production of the peripheral-type benzodiazepine receptor (PTBR) in astrocytes. PTBR, in turn, stimulates the conversion of cholesterol to pregnenolone to neurosteroids. Neurosteroids are then released from the astrocyte. They are capable of binding to their receptor within the neuronal GABA receptor complex and can increase inhibitory neurotransmission.

One recent study compared the levels of various chemicals in autopsied brain tissue from patients with cirrhosis who either died in hepatic coma or died without evidence of hepatic encephalopathy. Elevated levels of allopregnanolone, the neuroactive metabolite of pregnenolone, were found in the brain tissue of patients who died in hepatic coma. Brain levels of benzodiazepine receptor ligands were not significantly elevated in patients with or without coma. This work further bolsters the role of neurosteroids in hepatic encephalopathy.

Clinical features

Grading of the symptoms of hepatic encephalopathy is performed according to the so-called West Haven classification system:

  • Stage 0 – Minimal hepatic encephalopathy (previously known as subclinical hepatic encephalopathy). Lack of detectable changes in personality or behavior. Minimal changes in memory, concentration, intellectual function, and coordination. Asterixis is absent.
  • Stage 1 – Trivial lack of awareness. Shortened attention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria, depression, or irritability. Mild confusion. Slowing of ability to perform mental tasks. Asterixis can be detected.
  • Stage 2 – Lethargy or apathy. Disorientation. Inappropriate behavior. Slurred speech. Obvious asterixis. Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, and intermittent disorientation, usually regarding time.
  • Stage 3 – Somnolent but can be aroused, unable to perform mental tasks, disorientation about time and place, marked confusion, amnesia, occasional fits of rage, present but incomprehensible speech
  • Stage 4 – Coma with or without response to painful stimuli

In minimal hepatic encephalopathy, patients may have normal abilities in the areas of memory, language, construction, and pure motor skills. However, patients with minimal hepatic encephalopathy demonstrate impaired complex and sustained attention. They may have delays in choice reaction time. They may even have impaired fitness to drive. Typically, patients with minimal hepatic encephalopathy have normal function on standard mental status testing but abnormal psychometric testing. Neurophysiologic tests in common use are the number connection test, the digit symbol test, the block design test, and tests of reaction times to light or sound.

Patients with mild and moderate hepatic encephalopathy demonstrate decreased short-term memory and concentration upon mental status testing. They may show signs of asterixis, although the flapping tremor of the extremities is also observed in patients with uremia, pulmonary insufficiency, and barbiturate toxicity.

Some patients show evidence of fetor hepaticus, a sweet musty aroma of the breath that is believed to be secondary to the exhalation of mercaptans.

Other potential physical examination findings include hyperventilation and decreased body temperature.

Laboratory abnormalities

An elevated blood ammonia level is the classic laboratory abnormality reported in patients with hepatic encephalopathy. This finding may aid in correctly diagnosing patients with cirrhosis who present with altered mental status. However, serial ammonia measurements are inferior to clinical assessment in gauging improvement or deterioration in a patient under therapy for hepatic encephalopathy. Checking the ammonia level in a patient with cirrhosis who does not have hepatic encephalopathy has no utility. Only arterial or free venous blood specimens must be assayed when checking the ammonia level. Blood drawn from an extremity to which a tourniquet has been applied may provide a falsely elevated ammonia level when analyzed.

Classic EEG changes associated with hepatic encephalopathy are high-amplitude low-frequency waves and triphasic waves. However, these findings are not specific for hepatic encephalopathy. When seizure activity must be ruled out, an EEG may be helpful in the initial workup of a patient with cirrhosis and altered mental status.

Visual evoked responses also demonstrate classic patterns associated with hepatic encephalopathy. However, this test is not in common clinical use.

Computed tomography and magnetic resonance imaging studies of the brain may be important in ruling out intracranial lesions when the diagnosis of hepatic encephalopathy is in question. MRI has the additional advantage of being able to demonstrate hyperintensity of the globus pallidus on T1-weighted images, a finding that is commonly described in hepatic encephalopathy. This finding may correlate with increased manganese deposition within this portion of the brain.

Common precipitants

Some patients with a history of hepatic encephalopathy may have normal mental status while under treatment. Others have chronic memory impairment in spite of medical management. Both groups of patients are subject to episodes of worsened encephalopathy. Common precipitating factors are as follows:

Renal failure: Renal failure leads to decreased clearance of urea, ammonia, and other nitrogenous compounds.

Gastrointestinal bleeding: The presence of blood in the upper gastrointestinal tract results in increased ammonia and nitrogen absorption from the gut. Bleeding may predispose to kidney hypoperfusion and impaired renal function. Blood transfusions may result in mild hemolysis, with resulting elevated blood ammonia levels.

Infection: Infection may predispose to impaired renal function and to increased tissue catabolism, both of which increase blood ammonia levels.

Constipation: Constipation increases intestinal production and absorption of ammonia.

Medications: Drugs that act upon the central nervous system, such as opiates, benzodiazepines, antidepressants, and antipsychotic agents, may worsen hepatic encephalopathy.

Diuretic therapy: Decreased serum potassium levels and alkalosis may facilitate the conversion of NH4+ to NH3.

Dietary protein overload: This is an infrequent cause of hepatic encephalopathy.

Distinguishing hepatic encephalopathy from other acute and chronic causes of altered mental status may be difficult in patients with cirrhosis. A decision to perform additional neurologic studies should be based on the severity of the patient’s mental dysfunction, the presence of focal neurologic findings (observed infrequently in patients with hepatic encephalopathy), and the patient’s responsiveness to an empiric trial with cathartic agents. Even patients with severe hepatic encephalopathy should demonstrate steady improvement in mental dysfunction after an initiation of treatment with lactulose or cathartics derived from polyethylene glycol (PEG).

Differential diagnoses of encephalopathy

  • Intracranial lesions, such as subdural hematoma, intracranial bleeding, stroke, tumor, and abscess
  • Infections, such as meningitis, encephalitis, and intracranial abscess
  • Metabolic encephalopathy, such as hypoglycemia, electrolyte imbalance, anoxia, hypercarbia, and uremia
  • Hyperammonemia from other causes, such as secondary to ureterosigmoidostomy and inherited urea cycle disorders
  • Toxic encephalopathy from alcohol intake, such as acute intoxication, alcohol withdrawal, and Wernicke encephalopathy
  • Toxic encephalopathy from drugs, such as sedative hypnotics, antidepressants, antipsychotic agents, and salicylates
  • Organic brain syndrome
  • Postseizure encephalopathy

Management
The approach to the patient with hepatic encephalopathy depends upon the severity of mental status changes and upon the certainty of the diagnosis. As an example, a patient with known cirrhosis and mild complaints of decreased concentration might be served best by an empiric trial of lactulose and a follow-up office visit to check its effect. However, the patient presenting in hepatic coma requires a different approach. General management recommendations include the following:

  • Exclude nonhepatic causes of altered mental function.
  • Consider checking an arterial ammonia level in the initial assessment of a hospitalized patient with cirrhosis and with impaired mental function. Ammonia levels have less use in a stable outpatient.
  • Precipitants of hepatic encephalopathy, such as metabolic disturbances, gastrointestinal bleeding, infection, and constipation, should be corrected.
  • Avoid medications that depress central nervous system function, especially benzodiazepines. Patients with severe agitation and hepatic encephalopathy may receive haloperidol as a sedative. Treating patients who present with coexisting alcohol withdrawal and hepatic encephalopathy is particularly challenging. These patients may require therapy with benzodiazepines in conjunction with lactulose and other medical therapies for hepatic encephalopathy.
  • Patients with severe encephalopathy (ie, stage 3 or 4) who are at risk for aspiration should undergo prophylactic endotracheal intubation. They are optimally managed in the intensive care unit.

Most current therapies are designed to treat the hyperammonemia that is a hallmark of most cases of hepatic encephalopathy.

Treatments to decrease intestinal ammonia production

Diet

In the late 19th century, it was recognized that the feeding of a high-protein to dogs that had undergone portosystemic shunt surgery could produce symptoms of abnormal coordination and stupor in the treated animals.

In the 20th century, low-protein diets were routinely recommended for patients with cirrhosis, in hopes of decreasing intestinal ammonia production and of preventing exacerbations of hepatic encephalopathy. An obvious consequence was the worsening of preexisting protein-energy malnutrition. Protein restriction may be appropriate in some patients immediately following a severe flare of symptoms (ie, episodic hepatic encephalopathy). However, protein restriction is rarely justified in patients with cirrhosis and persistent hepatic encephalopathy. Indeed, malnutrition is a more serious clinical problem than hepatic encephalopathy for many of these patients.

In the author’s experience, it is the infrequent patient who is intolerant of a diet high in protein. Most patients with mild chronic hepatic encephalopathy tolerate more than 60-80 g of protein per day. Furthermore, one recent study administered a protein-rich diet (>1.2 g/kg/d) to patients with advanced disease awaiting liver transplantation, without inducing a flare of encephalopathy symptoms. Another study randomized patients with severe episodic encephalopathy to either a low-protein diet or a high-protein diet, administered via nasogastric tube. All patients received the same regimen of neomycin per nasogastric tube. Mental function improved at the same rate in both treatment groups. Importantly, patients receiving the low-protein diet had evidence for increased protein breakdown during the duration of the study.

Diets containing vegetable proteins appear to be better tolerated than diets rich in animal protein, especially proteins derived from red meats. This may be because of increased content of dietary fiber, a natural cathartic, and decreased levels of aromatic amino acids. Aromatic amino acids, as precursors for the false neurotransmitters tyramine and octopamine, are thought to inhibit dopaminergic neurotransmission and worsen hepatic encephalopathy.

The author recommends that patients consume well-cooked chicken and fish in addition to vegetable protein. Malnourished patients are encouraged to add commercially available liquid nutritional supplements to their diet. Patients infrequently require specialized treatment with oral or enteral supplements rich in branched-chain amino acids.

Cathartics

Lactulose (beta-galactosidofructose) and lactilol (beta-galactosidosorbitol) are nonabsorbable disaccharides that have been in common clinical use since the early 1970s (the latter is not available in the United States). They are degraded by intestinal bacteria to lactic acid and other organic acids.

Lactulose appears to inhibit intestinal ammonia production by a number of mechanisms. The conversion of Lactulose to lactic acid results in acidification of the gut lumen. This favors conversion of NH4+ to NH3 and the passage of NH3 from tissues into the lumen. Gut acidification inhibits ammoniagenic coliform bacteria, leading to increased levels of nonammoniagenic lactobacilli. Lactulose also works as a cathartic, reducing colonic bacterial load.

Initial lactulose dosing is 30 mL orally, daily or twice daily. The dose may be increased as tolerated. Patients should be instructed to reduce lactulose dosing in the event of diarrhea, abdominal cramping, or bloating. Patients should take sufficient lactulose as to have 2-4 loose stools per day.

Great care must be taken when prescribing lactulose. Overdosage can result in ileus, severe diarrhea, electrolyte disturbances, and hypovolemia. Hypovolemia may be sufficiently severe as to actually induce a flare of encephalopathy symptoms.

High doses of lactulose (eg, 30 mL q2-4h) may be administered orally or by nasogastric tube to patients hospitalized with severe hepatic encephalopathy. Lactulose may be administered as an enema to patients who are comatose and unable to take the medication by mouth. The recommended dosing is 300 mL lactulose plus 700 mL water, administered as a retention enema every 4 hours as needed. The author has had excellent success using PEG-containing colonic lavage solutions, such as Go-LYTELY administered via nasogastric tube, in the acute management of hospitalized patients with severe hepatic encephalopathy.

Lactulose has been the subject of dozens of clinical trials over almost 4 decades. Many small trials demonstrated the medication’s efficacy in the treatment of hepatic encephalopathy. However, one recent meta-analysis contradicts these trials and the author’s clinical experience. When assessing high-quality randomized trials, lactulose was no more effective than placebo at improving encephalopathy symptoms. In trials comparing lactulose to an antibiotic (eg, neomycin, rifaximin), lactulose was actually inferior to antibiotic therapy. This meta-analysis certainly forces reconsideration of the use of antibiotics, particularly rifaximin.

Antibiotics

Neomycin and other antibiotics, such as metronidazole, oral vancomycin, paromomycin, and oral quinolones, are administered in an effort to decrease the colonic concentration of ammoniagenic bacteria. Initial neomycin dosing is 250 mg orally 2-4 times a day. Doses as high as 4000 mg/d may be administered. Neomycin is usually reserved as a second-line agent, after initiation of treatment with lactulose. Long-term treatment with this oral aminoglycoside runs the risks of inducing ototoxicity and nephrotoxicity because of some systemic absorption.

Rifaximin (Xifaxan, Salix Pharmaceuticals, Inc, Morrisville, NC), a nonabsorbable derivative of rifampin, has been used in Europe for 18 years for a wide variety of gastrointestinal indications. It has also been used in the treatment of hepatic encephalopathy. In 2004, the drug received approval by the Food and Drug Administration (FDA) in the United States for the treatment of travelers’ diarrhea. In 2005, it received orphan drug status as a treatment for hepatic encephalopathy. In contrast to neomycin, its tolerability profile is comparable to placebo. Multiple clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactilol at improving hepatic encephalopathy symptoms. Similarly, rifaximin was as effective as neomycin and paromomycin. Rifaximin was better tolerated than both the cathartics and the other nonabsorbable antibiotics.

A number of concerns remain regarding rifaximin’s role in the treatment of hepatic encephalopathy. It remains to be determined if rifaximin can improve severe encephalopathy symptoms as rapidly as lactulose.

There are also concerns regarding the cost-effectiveness of the medication. At the author’s institution, one day’s treatment with lactulose (30 g PO qid) costs $2.20; one day’s treatment with rifaximin (400 mg PO tid) costs $18.42. However, the differential in cost of medication might be overcome if it was determined that rifaximin decreased the incidence of significant medication-related adverse effects (eg, severe abdominal cramping) or reduced hospital stay.

It also needs to be determined if rifaximin is effective at a lower dose (eg, 400 mg PO bid). Similarly, investigators need to study whether patients with persistent, mild encephalopathy can be given a drug “holiday” (eg, discontinue treatment for 1 week out of 4 weeks). There are also questions whether long-term treatment with rifaximin can induce microbial resistance. Thus far, microbial resistance has not been reported with the use of the medication.

Treatments to increase ammonia clearance

L-ornithine L-aspartate (LOLA)

LOLA (Hepa-Merz, Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany) is available in Europe in both intravenous formulations and oral formulations. It is not available in the United States. LOLA is a stable salt of the 2 constituent amino acids. L-ornithine stimulates the urea cycle, with resulting loss of ammonia. Both l-ornithine and l-aspartate are substrates for glutamate transaminase. Their administration results increased glutamate levels. Ammonia is subsequently used in the conversion of glutamate to glutamine by glutamine synthetase. LOLA was found to be effective in treating hepatic encephalopathy in a number of European trials.

Zinc

Zinc deficiency is common in cirrhosis. Even in patients who are not zinc deficient, zinc administration has the potential to improve hyperammonemia by increasing the activity of ornithine transcarbamylase, an enzyme in the urea cycle. The subsequent increase in ureagenesis results in the loss of ammonia ions.

Zinc sulfate and zinc acetate have been used at a dose of 600 mg orally every day in clinical trials. Hepatic encephalopathy improved in 2 studies; there was no improvement in mental function in 2 other studies.

Sodium benzoate, sodium phenylbutyrate, sodium phenylacetate

Sodium benzoate interacts with glycine to form hippurate. The subsequent renal excretion of hippurate results in the loss of ammonia ions. Dosing of sodium benzoate at 5 g orally twice a day can effectively control hepatic encephalopathy. Use of the medication is limited by the risk of salt overload and by its unpleasant taste. The medication, also used as a food preservative, is available through many specialty chemical manufacturers throughout the United States. The author has limited its use to patients with severe encephalopathy symptoms.

Sodium phenylbutyrate is converted to phenylacetate. Phenylacetate, in turn, reacts with glutamine to form phenylacetylglutamine. This chemical is subsequently excreted in the urine, with loss of ammonia ions. Sodium phenylbutyrate (Buphenyl, Ucyclyd Pharma, Scottsdale, Ariz) and intravenous sodium phenylacetate in combination with sodium benzoate (Ammonul, Ucyclyd Pharma, Scottsdale, Ariz) are approved by the FDA for the treatment of hyperammonemia associated with urea cycle disorders. These medications have not yet been subjected to clinical trials in patients with cirrhosis and with hyperammonemia and hepatic encephalopathy.

L-carnitine

L-carnitine improved hepatic encephalopathy symptoms in several small studies of patients with cirrhosis. Whether the medication works by improving blood ammonia levels or whether it works centrally perhaps by decreasing brain ammonia uptake remains unclear.

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http://www.abc.net.au/news/stories/2008/03/26/2199424.htm

Pot bellies ‘triple dementia risk’

Having a large belly in middle age nearly triples the risk of developing dementia, a study has found.

“Considering that 50 per cent of adults in this country (United States) have abdominal obesity, this is a disturbing finding,” said study author Rachel Whitmer of the Kaiser Permanente Division of Research in Oakland, California.

Being overweight in midlife and beyond has long been linked to increased risk for disease such as stroke, diabetes and heart disease.

This is the first study to link excess fat to dementia and, interestingly, excess abdominal fat increased the risk even among those who were of normal weight overall.

Researchers measured the abdominal fat of 6,583 people age 40 to 45 in northern California and some 36 years later 16 per cent had developed dementia, the study published in the journal Neurology found.

Those who were overweight or obese but did not have a pot belly had an 80 per cent increase in the risk of dementia compared to people with a normal body weight and abdominal fat level.

Increased risk

The risk increase jumped by 230 per cent among overweight people with a large belly and 360 per cent among the obese with large abdomens.

“Where one carries the weight – especially in midlife – appears to be an important predictor for dementia risk,” Ms Whitmer said.

While more research is needed to understand why this link exists, it is possible that the abdominal obesity is part of a complex set of health-related behaviors that increase the risk of dementia.

“Autopsies have shown that changes in the brain associated with Alzheimer’s disease may start in young to middle adulthood, and another study showed that high abdominal fat in elderly adults was tied to greater brain atrophy,” she said.

“These findings imply that the dangerous effects of abdominal obesity on the brain may start long before the signs of dementia appear.”

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Yolgnu leaders want to take control of community health

A number of senior Yolgnu leaders say they’ve united to present a stronger voice on Indigenous health policies and to reduce the unsatisfactory level of deaths by disease and suicide in the region.

Yolgnu law man Galarrwuy Yunupingu, Northern Land Council chairman Wali Wanungmurra and Miwatj Health chairman John Morgan are some of the group who say they’re continually frustrated by the way health services are delivered in north-east Arnhem Land.

The CEO of the Miwatj Health Service Eddie Mulholland says the Territory and Federal Governments they must better consult Yolgnu people if they want to deliver improved health outcomes in the region.

“They want the way that the health services are delivered determined by them … and the end results should be the desires of the local people. That’s what local control is all about. So I guess in some sense this is sending a message.

“It’s time they were given the opportunity to take responsibility for things they have always been blamed for failing in but had no responsibility for such.”

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