Alcohol, Not Marijuana, Linked to Liver Injury in Women With Both HIV and Hepatitis C
Hepatitis C virus (HCV) infects the liver and can cause inflammation. If the infection becomes chronic, the struggle between the virus and the immune system results in healthy liver tissue being replaced with useless scar tissue in a process called fibrosis. Over time, more of the liver becomes injured and, if left untreated, HCV infection can result in scar tissue encompassing the liver, leading to serious complications, liver failure and an increased risk for liver cancer. In caring for patients who have HCV infection (with or without HIV co-infection), doctors have been examining potential factors that could speed up the rate of scar tissue forming.
One well-known risk factor for liver injury among people with HCV is alcohol consumption. In the past decade, researchers have been investigating other potential factors such as marijuana use.
Studies of different designs have produced conflicting findings about the safety of marijuana in people co-infected with HIV and HCV. To find clarity on this issue, researchers in the U.S. analysed data collected from a long-term study on the health of women. During the study, women were surveyed about substance use and their liver health was regularly assessed. The researchers found that over a period of about 11 years use of marijuana was not linked to any increased risk for scarring of the liver among women with HIV-HCV co-infection. However, they did find that alcohol use was linked to an increased risk for the formation of scar tissue within the liver.
Receptors and HCV
Cells of the body have proteins on their surface called receptors. These receptors interact with different substances, including other proteins and chemical messengers. Cells in different organ-systems have receptors for cannabinoids. This is the term used for compounds found in marijuana and similar compounds produced by the body. The body produces cannabinoids in very small amounts and these attach to receptors specially designed to bind to cannabinoids.
There are two main types of such receptors -- CB1 and CB2. The CB1 receptors are found in high concentrations in the brain and also on liver, intestine and fat cells. The CB2 receptors are found mainly on cells of the immune system and also the liver. When the body produces cannabinoids (or someone consumes marijuana, which contains cannabinoids), these compounds bind to CB1 and CB2 and affect the activity of cells.
Some people with HCV infection use marijuana and some doctors have wondered about the potential effect of this herb on the health of the liver. A possible reason underpinning their concern is that HCV infection causes liver cells to have increased amounts of receptors for cannabinoids. In theory, this could make the livers of people with HCV infection more sensitive to any effects of the compounds in marijuana.
Researchers at major clinics in Baltimore, Chicago, New York and San Francisco have been collaborating on a large study called WIHS (pronounced "wise") to monitor the health of women at high risk for and who have HIV infection. Some of the women with HIV are also co-infected with HCV. Women participating in WIHS are regularly monitored, undergo interviews, get physical exams and have blood drawn every six months for analysis. All of this data is collected and periodically analysed for different trends.
Women were recruited for WIHS during the following periods:
- 1994 to 1995
- 2001 to 2002
- 2011 to 2012
For the purposes of the present analysis on marijuana use, researchers focused on data collected from 575 women (out of a possible 4,137) who had both HIV and HCV. The average profile of the women upon entering the study was as follows:
- age -- 40 years
- the most common strain, or genotype, of HCV was genotype 1 (found in 88% of women)
- HCV viral load -- 6.1 logs
- HIV viral load -- 4.1 logs (only 6% of the women were taking ART when they entered the study)
- CD4+ count -- 375 cells/mm3
- 30% had higher-than-normal blood pressure
- 18% had type-2 diabetes
- 80% smoked tobacco
- 23% injected street drugs
- length of time in the study -- 11 years
Researchers used a formula called FIB-4 to estimate the degree of scarring of the liver. The formula for estimating FIB-4 requires a person's age and the following blood test results:
- the liver enzyme AST
- the liver enzyme ALT
The initial studies used to develop FIB-4 and compare it to the results of liver biopsies were done in more than 1,200 patients. Subsequently, research teams in high-income countries have also performed independent investigations of FIB-4 and its relation to liver fibrosis in several thousand patients. These teams have found that, overall, while FIB-4 is not perfect, it can be a useful and general guide to the degree of scarring in the liver.
Results -- Marijuana Use
- 11% of participants reported using marijuana once weekly in the past six months
- 6% of participants reported using marijuana daily in the past six months
The researchers stated that 67% of women in the study "abstained from [marijuana] or [used it] less than weekly for the entire duration of [monitoring]."
When researchers compared women who used marijuana to women who did not use marijuana, there was no significant link between marijuana use and an increased risk for scarring of the liver. This was the case whether or not women used marijuana daily or less frequently. It was also the case regardless of the number of years women used marijuana.
Focus on Fibrosis
Over the course of the study, 51% of the women developed a significant degree of scarred liver tissue (graded as F3 to F4). The researchers found that the following factors were significantly associated with worsening liver injury:
- higher FIB-4 score upon entering the study
- lower CD4+ cell count upon entering the study
- alcohol use over the course of the study
These findings make sense, as the higher FIB-4 score would indicate more liver injury than a lower FIB-4 score. Past research has found that untreated HIV infection (suggested here by a lower CD4+ count) is linked to a faster rate of liver injury in co-infected people.
Finally, alcohol is a well-known risk factor for liver injury. The researchers stated that "overall alcohol use at study entry was low." However, the researchers found that 19% of women had "heavy alcohol use" when they entered the study, which they defined as more than seven alcoholic drinks per week. During their last visit to a study clinic, researchers found that 9% of women reported heavy alcohol use.
It is possible that some women did not disclose the full extent of their use of alcohol and marijuana.
Neither liver biopsies nor fibro scans of the liver were performed to assess fibrosis. However, such procedures would have added to the study's complexity and cost. Although FIB-4 is imperfect, it can be a useful way of indirectly assessing the degree of scarring in this organ.
According to the researchers, there was "a relatively small number of heavy [marijuana] users." It is possible that this could have somehow inadvertently biased the conclusions reached in this study. However, the long period of monitoring liver fibrosis, coupled with an equally long period of marijuana use, add strength to the study's findings.
In summary, no matter what type of relevant statistical analysis was used, the researchers stated: "We found no evidence that [marijuana] use increases the risk of [worsening] liver fibrosis in women with HIV-HCV co-infection."
- Kelly EM, Dodge JL, Sarkar M, et al. Marijuana use is not associated with progression to advanced liver fibrosis in HIV/HCV co-infected women. Clinical Infectious Diseases. 2016; in press.
- van der Poorten D, Shahidi M, Tay E, et al. Hepatitis C virus induces the cannabinoid receptor 1. PLoS One. 2010 Sep 17;5(9). pii: e12841.
- Turcotte C, Chouinard F, Lefebvre JS, et al. Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites. Journal of Leukocyte Biology. 2015 Jun;97(6):1049-70.
- Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection: comparison with liver biopsy and fibrotest. Hepatology. 2007 Jul;46(1):32-6.
- Holmberg SD, Lu M, Rupp LB, et al. Noninvasive serum fibrosis markers for screening and staging chronic hepatitis C virus patients in a large US cohort. Clinical Infectious Diseases. 2013 Jul;57(2):240-6.
- Marcellin F, Lions C, Rosenthal E, et al. No significant effect of cannabis use on the count and percentage of circulating CD4 T-cells in HIV-HCV co-infected patients (ANRS CO13-HEPAVIH French cohort). Drug and Alcohol Review. 2016; in press.
- Basu PP, Aloysius MM, Shah NJ, et al. The endocannabinoid system in liver disease, a potential therapeutic target. Alimentary Pharmacology & Therapeutics. 2014 Apr;39(8):790-801.
- Taylor AL, Denniston MM, Klevens RM, et al. Association of hepatitis C virus with alcohol use among U.S. adults: NHANES 2003-2010. American Journal of Preventive Medicine. 2016; in press.
- Kim HN, Nance R, Van Rompaey S, et al. Poorly controlled HIV infection: An independent risk factor for liver fibrosis. Journal of Acquired Immune Deficiency Syndromes. 2016; in press.