Increased intestinal permeability is central to alcoholic hepatitis

CHICAGO – Why is it that only about 20% of individuals who consume 10 or more alcoholic drinks daily for years on end will develop alcoholic hepatitis?

New insight into the mechanism of this disease points to markedly increased intestinal permeability as playing a key role. Increased intestinal permeability is consistently present in patients with alcoholic hepatitis, but not in heavy drinkers without the disease or in normal healthy controls, Dr. George Holman reported at the annual Digestive Disease Week.

"Our study suggests that intestinal permeability is disrupted in alcoholic hepatitis. We speculate that increased intestinal permeability allows passage of lipopolysaccharides from gut bacteria into the serum. These endotoxins are carried to the liver and cause subsequent hepatic inflammation," according to Dr. Holman of the University of New Mexico, Albuquerque.

Alcoholic hepatitis is characterized by steatohepatitis and rapid clinical decompensation. It is typically seen only in patients who have consumed more than 100 g of alcohol – that’s roughly 10 drinks – daily for years.

Dr. Holman presented a prospective case-control study involving 22 patients hospitalized for severe alcoholic hepatitis and 33 healthy volunteers. The study hypothesis was that patients with alcoholic hepatitis have defective intestinal barrier function which allows gut-derived bacterial endotoxins, known as lipopolysaccharides, to enter the systemic circulation, leading to a resultant inflammatory response in the liver.

To test this hypothesis, the investigators utilized urinary excretion of lactulose and mannitol as intestinal permeability markers. They also measured serum lipopolysaccharide levels as well as circulating levels of the proinflammatory cytokines interleukin-6 and tumor necrosis factor–alpha.

The alcoholic hepatitis group showed on average an eightfold increase in intestinal permeability as measured by the lactulose/mannitol excretion ratio, compared with controls. Also, a near-perfect linear correlation was found between the degree of intestinal permeability and the magnitude of the elevation in serum lipopolysaccharide levels. Paralleling these increases in intestinal permeability and lipopolysaccharides, serum levels of interleukin-6 and tumor necrosis factor–alpha were also significantly higher in the alcoholic hepatitis patients than in controls. These data, taken as a whole, point to increased intestinal permeability as a pathogenic factor resulting in endotoxemia and immune activation, he said.

Also worthy of note, intestinal permeability tracked with MELD (model for end-stage liver disease) scores such that as intestinal permeability increased, MELD scores climbed nearly exponentially, Dr. Holman continued.

Audience members wondered whether treating alcoholic hepatitis patients, typically with prednisone or pentoxifylline, had a favorable impact upon their abnormal intestinal permeability. Dr. Holman replied that although he and his coinvestigators had planned to look at this issue, follow-up simply wasn’t possible. This was a very sick patient cohort – their mean alcohol consumption was 26 drinks daily for years – and despite treatment, nearly half of them were dead within several months. However, other investigators have previously shown that alcoholic hepatitis patients who respond favorably to treatment and are able to leave the hospital show a decrease in their previously high endotoxin levels, while more severely affected patients do not.

The cause of the defective intestinal barrier that figures prominently in alcoholic hepatitis remains a mystery. Other studies have shown that individuals who drink heavily without developing alcoholic liver injury don’t have increased intestinal permeability. Thus, increased intestinal permeability is not caused by heavy alcohol use. Some other as yet unidentified factor must be causing it, Dr. Holman concluded.

This study was supported by university research funds. Dr. Holman reported having no financial conflicts.

bjancin@frontlinemedcom.com

CHICAGO – Why is it that only about 20% of individuals who consume 10 or more alcoholic drinks daily for years on end will develop alcoholic hepatitis?

New insight into the mechanism of this disease points to markedly increased intestinal permeability as playing a key role. Increased intestinal permeability is consistently present in patients with alcoholic hepatitis, but not in heavy drinkers without the disease or in normal healthy controls, Dr. George Holman reported at the annual Digestive Disease Week.

"Our study suggests that intestinal permeability is disrupted in alcoholic hepatitis. We speculate that increased intestinal permeability allows passage of lipopolysaccharides from gut bacteria into the serum. These endotoxins are carried to the liver and cause subsequent hepatic inflammation," according to Dr. Holman of the University of New Mexico, Albuquerque.

Alcoholic hepatitis is characterized by steatohepatitis and rapid clinical decompensation. It is typically seen only in patients who have consumed more than 100 g of alcohol – that’s roughly 10 drinks – daily for years.

Dr. Holman presented a prospective case-control study involving 22 patients hospitalized for severe alcoholic hepatitis and 33 healthy volunteers. The study hypothesis was that patients with alcoholic hepatitis have defective intestinal barrier function which allows gut-derived bacterial endotoxins, known as lipopolysaccharides, to enter the systemic circulation, leading to a resultant inflammatory response in the liver.

To test this hypothesis, the investigators utilized urinary excretion of lactulose and mannitol as intestinal permeability markers. They also measured serum lipopolysaccharide levels as well as circulating levels of the proinflammatory cytokines interleukin-6 and tumor necrosis factor–alpha.

The alcoholic hepatitis group showed on average an eightfold increase in intestinal permeability as measured by the lactulose/mannitol excretion ratio, compared with controls. Also, a near-perfect linear correlation was found between the degree of intestinal permeability and the magnitude of the elevation in serum lipopolysaccharide levels. Paralleling these increases in intestinal permeability and lipopolysaccharides, serum levels of interleukin-6 and tumor necrosis factor–alpha were also significantly higher in the alcoholic hepatitis patients than in controls. These data, taken as a whole, point to increased intestinal permeability as a pathogenic factor resulting in endotoxemia and immune activation, he said.

Also worthy of note, intestinal permeability tracked with MELD (model for end-stage liver disease) scores such that as intestinal permeability increased, MELD scores climbed nearly exponentially, Dr. Holman continued.

Audience members wondered whether treating alcoholic hepatitis patients, typically with prednisone or pentoxifylline, had a favorable impact upon their abnormal intestinal permeability. Dr. Holman replied that although he and his coinvestigators had planned to look at this issue, follow-up simply wasn’t possible. This was a very sick patient cohort – their mean alcohol consumption was 26 drinks daily for years – and despite treatment, nearly half of them were dead within several months. However, other investigators have previously shown that alcoholic hepatitis patients who respond favorably to treatment and are able to leave the hospital show a decrease in their previously high endotoxin levels, while more severely affected patients do not.

The cause of the defective intestinal barrier that figures prominently in alcoholic hepatitis remains a mystery. Other studies have shown that individuals who drink heavily without developing alcoholic liver injury don’t have increased intestinal permeability. Thus, increased intestinal permeability is not caused by heavy alcohol use. Some other as yet unidentified factor must be causing it, Dr. Holman concluded.

This study was supported by university research funds. Dr. Holman reported having no financial conflicts.

bjancin@frontlinemedcom.com

CHICAGO – Why is it that only about 20% of individuals who consume 10 or more alcoholic drinks daily for years on end will develop alcoholic hepatitis?

New insight into the mechanism of this disease points to markedly increased intestinal permeability as playing a key role. Increased intestinal permeability is consistently present in patients with alcoholic hepatitis, but not in heavy drinkers without the disease or in normal healthy controls, Dr. George Holman reported at the annual Digestive Disease Week.

"Our study suggests that intestinal permeability is disrupted in alcoholic hepatitis. We speculate that increased intestinal permeability allows passage of lipopolysaccharides from gut bacteria into the serum. These endotoxins are carried to the liver and cause subsequent hepatic inflammation," according to Dr. Holman of the University of New Mexico, Albuquerque.

Alcoholic hepatitis is characterized by steatohepatitis and rapid clinical decompensation. It is typically seen only in patients who have consumed more than 100 g of alcohol – that’s roughly 10 drinks – daily for years.

Dr. Holman presented a prospective case-control study involving 22 patients hospitalized for severe alcoholic hepatitis and 33 healthy volunteers. The study hypothesis was that patients with alcoholic hepatitis have defective intestinal barrier function which allows gut-derived bacterial endotoxins, known as lipopolysaccharides, to enter the systemic circulation, leading to a resultant inflammatory response in the liver.

To test this hypothesis, the investigators utilized urinary excretion of lactulose and mannitol as intestinal permeability markers. They also measured serum lipopolysaccharide levels as well as circulating levels of the proinflammatory cytokines interleukin-6 and tumor necrosis factor–alpha.

The alcoholic hepatitis group showed on average an eightfold increase in intestinal permeability as measured by the lactulose/mannitol excretion ratio, compared with controls. Also, a near-perfect linear correlation was found between the degree of intestinal permeability and the magnitude of the elevation in serum lipopolysaccharide levels. Paralleling these increases in intestinal permeability and lipopolysaccharides, serum levels of interleukin-6 and tumor necrosis factor–alpha were also significantly higher in the alcoholic hepatitis patients than in controls. These data, taken as a whole, point to increased intestinal permeability as a pathogenic factor resulting in endotoxemia and immune activation, he said.

Also worthy of note, intestinal permeability tracked with MELD (model for end-stage liver disease) scores such that as intestinal permeability increased, MELD scores climbed nearly exponentially, Dr. Holman continued.

Audience members wondered whether treating alcoholic hepatitis patients, typically with prednisone or pentoxifylline, had a favorable impact upon their abnormal intestinal permeability. Dr. Holman replied that although he and his coinvestigators had planned to look at this issue, follow-up simply wasn’t possible. This was a very sick patient cohort – their mean alcohol consumption was 26 drinks daily for years – and despite treatment, nearly half of them were dead within several months. However, other investigators have previously shown that alcoholic hepatitis patients who respond favorably to treatment and are able to leave the hospital show a decrease in their previously high endotoxin levels, while more severely affected patients do not.

The cause of the defective intestinal barrier that figures prominently in alcoholic hepatitis remains a mystery. Other studies have shown that individuals who drink heavily without developing alcoholic liver injury don’t have increased intestinal permeability. Thus, increased intestinal permeability is not caused by heavy alcohol use. Some other as yet unidentified factor must be causing it, Dr. Holman concluded.

This study was supported by university research funds. Dr. Holman reported having no financial conflicts.

bjancin@frontlinemedcom.com