Liver diseases

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NASH

In light of the close relationship between the liver and the intestinal tract, the intestinal microbiota can influence the onset of hepatic diseases, including non-alcoholic steatohepatitis (NASH).

NASH is characterized by abnormal liver-function parameters (increased blood transaminase or γGT levels) and histological anomalies in the hepatic tissue, such as steatosis, ballooning hepatocytes (increased hepatocyte size and transparency) and lobe inflammation. Although it does not appear in the histological picture for NASH, fibrosis (accumulation of extracellular matrix in the hepatic parenchyma) is considered to be a negative prognostic factor for the disease1.

A silent disease

NASH incidence varies widely according to ethnicity but is found in every country2. Most often asymptomatic, the diagnosis can only be confirmed by an invasive hepatic biopsy. 

Linked to dysbiosis

The liver, supplied by the portal vein, is exposed to nutrients, toxins and microorganisms from the gastrointestinal tract, including certain proinflammatory Gram-negative bacteria3. Notably, study results showed increased intestinal permeability in patients with NASH4 that increases the liver’s exposure to pathogenic and proinflammatory elements from the gastrointestinal tract. They also have dysbiosis, with more Firmicutes and fewer Bacteroidetes present5, which seems to demonstrate an association between dysbiosis and NASH.

Those observations suggest NASH might be managed by reestablishing the microbiota equilibrium: it was also shown that a combination of prebiotics and probiotics (synbiotics) improves histological criteria in NASH more effectively than lifestyle changes6. An idea to be pursued, for sure!

 

Sources:
1. World Gastroenterology Organisation Global Guidelines - Stéatose hépatique non alcoolique et stéato-hépatite non alcoolique http://www.worldgastroenterology.org/UserFiles/file/guidelines/nafld-nash-french-2012.pdf 
2. Marchesini G. et al. J Clin Endocrinol Metab. 2008;93(11 Suppl 1):S74-80 https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2008-1399 
3. Bieghs V et al. Innate immune signaling and gut-liver interactions in non-alcoholic fatty liver disease. Hepatobiology Surg Nutr 2014;3:377-85. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273113/
4. Miele et al. Increased intetinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009;49:1877-87. https://www.ncbi.nlm.nih.gov/pubmed/19291785
5. Ley et al. Obesity alters gut microbioal ecology. PNAS 2005;102:11070-5. 
6. Buffet C. Bull. Acad. Natle Méd., 2014, 198, no 9, 1641-1652, séance du 9 décembre 2014 http://www.academie-medecine.fr/wp-content/uploads/2016/06/1641-à-1652.pdf 

Cirrhosis

Cirrhosis is a chronic disease whose methods for diagnosis remain invasive. Its management could include analysis of the intestinal microbiota.

Cirrhosis results from an unknown pathogenesis, characterized by pernicious fibrosis that destroys the normal liver architecture, isolating abnormally structured hepatocyte nodules1. That process leads to loss of liver function. Approximately 700,000 cirrhosis cases are diagnosed annually in France, with 30% at a severe stage, leading to 10,000 to 15,000 deaths2. Its prevalence is about the same in developed countries, and higher in Africa and Asia where hepatitis B and C are endemic3.

Causes and diagnoses 

Although alcoholism is the most common cirrhosis etiology, it can also be caused by chronic hepatitis B or C virus (HBV/HBC) infection, metabolic syndrome, hemochromatosis, or autoimmune liver disease (particularly primary biliary cirrhosis)1.

Cirrhosis diagnosis relies on a liver biopsy to evaluate its stage.

Dysbiosis identified

Based on a 2011 report4, cirrhosis was associated with intestinal dysbiosis, with fewer Bacteroidetes and more Proteobacteria and Fusobacteria in gut flora. That study also found enhanced Prevotellaceae presence in patients with alcoholic cirrhosis, compared to those whose cirrhosis attributable to HBV infection. A defined cirrhosis dysbiosis ratio (CDR)5 of 2 for healthy individuals, rapidly declines for cirrhotic patients, to 0.9 for compensated cirrhosis and 0.3 for a patient with an infectious episode. The CDR might be used to evaluate prognosis. 

Metagenomics for a diagnosis?

Lastly, a metagenomic study analyzing all the genes carried by intestinal bacteria showed a specific cirrhosis-associated dysbiosis: other than certain genes associated with disease severity, researchers found that fewer bacterial genes indicated the presence of cirrhosis6. Could adopting this analytical technique be a less invasive diagnosis of the disease?

 

Sources:
1. HAS. Synthèses des recommandations professionnelles. Critères diagnostiques et bilan initial de la cirrhose non compliquée. 2006. http://www.has-sante.fr/portail/upload/docs/application/pdf/fs_cirrhose_web.pdf 
2 . http://www.inserm.fr/index.php/thematiques/physiopathologie-metabolisme-nutrition/dossiers-d-information/cirrhose
3 - Liver cirrhosis. Schuppan D. et al. Liver cirrhosis. Lancet 2008 8;371(9615):838-51 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2271178/ 
4. Chen et al. Charakterisation of fecal microbial communities in patients with livers cirrhosis. Hepatology 2011;54:562-72. https://www.ncbi.nlm.nih.gov/pubmed/21574172
5. Bajaj JS et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014;60:940-7. https://www.ncbi.nlm.nih.gov/pubmed/24374295 
6. Qin et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014;513:59-64. https://www.ncbi.nlm.nih.gov/pubmed/25079328

Hepatocellular carcinoma

In almost 90% of cases, hepatocellular carcinoma develops in cirrhotic livers. Intestinal microbiota seems to play an important in this development. 

According to the World Health Organization (WHO), liver cancer was responsible for the deaths of 745,000 people in 20121. This kind of cancer develops in cirrhotic livers, most often as a result of chronic alcoholism or following chronic viral hepatitis. But not all patients with cirrhosis develop hepatocellular carcinoma. What conditions promote the appearance of this cancer?

Chronic inflammation or deteroriation in the intestinal barrier

The intestinal microbiota seems to be involved in the development of hepatocellular carcinoma. A specific dysbiosis brought on by alcohol seems to lead to this chronic inflammation. Absorbed alcohol is metabolized by intestinal bacteria into acetaldehyde, which alters the intestinal barrier. The increase in intestinal permeability promotes the passage of pro-inflammatory molecules and the passage of bacterial toxins to the liver through the portal circulation. The latter are responsible for the onset of hepatic inflammation3.

An avenue to prevent liver cancer

The study of the composition of the gastrointestinal microbiota could present a diagnostic tool to identify people at risk for liver cancer. Preventive treatments could then be offered to modify the gastrointestinal microbiota by reducing the number of harmful bacteria involved in the onset of liver injuries, and promoting the number of protective bacteria (diet, probiotics, and more)4

 

Sources:
1 – OMS février 2015 http://www.who.int/mediacentre/factsheets/fs297/fr/
2 - Sherman M. Epidemiology of hepatocellular carcinoma. Oncology 2010; 78:7-10.  https://www.ncbi.nlm.nih.gov/pubmed/20616577
3 - Dapito DH et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer cell 2012; 21 : 504-16. https://www.ncbi.nlm.nih.gov/pubmed/22516259
4 -  Gratz S et al. Lactobacillus rhamnosus strain GG modulates intestinal absorption, fecal excretion, and toxicity of aflatoxin B(1) in rats. Appl Environ Microbiol 2006 ; 72 : 7398-400. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1636196/

Alcoholic liver disease

The unequal risk of alcoholic liver disease (ALD) suggests that cofactors are involved in the development of the disease. Recent research tends to show the role of microbiota in developing the disease.

Alcohol consumption is responsible for 3.8% of deaths worldwide and 4.6% of the loss of years of life due to premature death1. As for alcoholic liver disease (ALD) itself, there is no direct way to calculate its epidemiology. We can get picture of the disease by studying the mortality rate from hepatic cirrhosis, although bearing in mind that it is difficult to make a distinction between alcoholic and non-alcoholic cirrhosis2

Associated diseases and pathologies

ALD is diagnosed when excessive consumption of alcohol (more than 30 g/day)1 is observed along with clinical and biological signs indicating steatosis, alcoholic steatohepatitis (ASH), progressive fibrosis, cirrhosis, or even the early signs of hepatocellular cancer.

Role of microbiota

The influence of microbiota on ALD has been known since 1995: it has been observed that the alteration in microbiota produced by antibiotics protects rats from hepatic lesions due to alcohol3. On the one hand, microbiota transforms alcohol into acetaldehyde, which alters the intestinal barrier4 and increases the permeability of the intestinal wall; on the other hand, an increase in the concentration of polysaccharides leads to hepatic inflammation5

Alcohol and dysbiosis: a connection

The chronic ingestion of ethanol causes dysbiosis in rodents, with a reduction in bacteria of the genera Lactobacillus, Pediococcus, Leuconostoc, and Lactococcus6, and an increase in Proteobacteria and Actinobacteria7. In humans, observations have shown an alteration of the microbiota in alcoholic patients, with a reduction in Bacteroidetes and an increase in Enterobacteriaceae and Proteobacteria8

Beyond its role in hepatic lesions, the microbiota also seems to influence psychological and psychiatric symptoms associated with ALD9. Its role should not be neglected in treating patients.

 

Sources:
1.    Directives de pratique clinique de l’EASL: Prise en charge de la maladie alcoolique du foie - Association européenne pour l’étude du foie (EASL) - Journal of Hepatology 2012 vol. 57 | 399–420 
2.    Rehm J et al. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 2009;373:2223–2233. https://www.ncbi.nlm.nih.gov/pubmed/19560604 
3.    Adachi Y et al. Antibiotics prevents liver injury in rats following long-term exposure to ethanol. Gastroenterlogy 1995 ; 108 : 218-24. https://www.ncbi.nlm.nih.gov/pubmed/7806045 
4.    Ferrier L. et al. Impairement of the intestinal barrier by ethanol involves enteric microflora and mast cell activation in rodents. Am J Pathol 2006 ; 168 : 1148-54. https://www.ncbi.nlm.nih.gov/pubmed/16565490 
5.    Mencin et al. Toll-like receptors as targets in chronic liver disease. Hepatology 2009 ; 50 : 638-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721430/ 
6.    Yan et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 2011 ; 53 : 96-105. https://www.ncbi.nlm.nih.gov/pubmed/21254165 
7.    Bull-Otterson L. et al. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome ad the effet of Lactobacillus rhamnosus GG treatment. PloS One 2013 ; 8 : e53028. https://www.ncbi.nlm.nih.gov/pubmed/23326376 
8.    Mutlu et al. Colonic microbiome is altered in alcoholism. Am J Physiol Gastrointest Liver Physiol 2012 ; 302 : G966-978. https://www.ncbi.nlm.nih.gov/pubmed/22241860 
9.    Leclercq S et al. Intestinal permeability, gut-microbial dysbiosis and behavioral merkers of alcohol-dependence severity. PNAS 2014; 111 : E4485-93. http://www.pnas.org/content/111/42/E4485.full 

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