Association Between Smoking and Outcomes of Autoimmune Hepatitis

Background Autoimmune hepatitis (AIH) is a chronic liver disorder caused by the immune system targeting liver cells. The etiology of AIH remains undefined. Therefore, we aim to explore the relationship between cigarette smoking and AIH. Methods A retrospective study was done at the Department of Medicine, King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia. Forty-six inpatients and outpatients managed at KAUH from 2016 to 2021 and diagnosed with AIH were included. Data about patients’ age, gender, smoking state, type of liver disease, and any other autoimmune disease were collected. Results In all, 10.9% (n = 5) of patients were active smokers, and 60.0% (n = 3) used cigarettes. The median number of cigarettes smoked per day was 17, while 56.5% (n = 26) had a positive family history of smoking, and 41.3% (n = 19) were passive smokers. Of them, 39.1% (n = 18) had at least one complication of AIH, such as liver cirrhosis, which is the most frequent complication (61.1%; n = 11), followed by esophageal varices (22.2%; n = 4), liver fibrosis (5.6%; n = 1), and fatty liver (5.6%; n = 1). The presence of any complication was not associated with patients’ demographics or smoking status. On the other hand, liver cirrhosis was significantly higher among currently active smokers. Conclusion No relationship was found between smoking and the AIH outcomes. Future multi-center studies on larger samples are needed.


Introduction
Autoimmune hepatitis (AIH) is a severe inflammatory liver disease that affects children and adults worldwide.It causes histological, biochemical, and serological changes that result in the autoimmunemediated destruction of the liver cells.The etiology of AIH is unclear, but over time, it was seen that genetics, environmental factors, and history of being infected with certain organisms triggered the disease [1,2].
Smoking is a major factor in many pathological conditions and has been linked to the development of various autoimmune diseases.Also, it contains numerous toxic, carcinogenic, stable and unstable free radicals, reactive oxygen species (ROS), and mutagenic chemicals that cause biological oxidative damage.Continuous exposure to these chemicals leads to an immense amount of damage to human health [3,4].
Smoking also has a role in autoimmune diseases by induction of oxidative stress that leads to dysregulating DNA demethylation, upregulation of immune genes, and leading to autoreactivity, which is responsible for the development of autoimmune diseases such as AIH [5][6][7].
There is no data on the association between AIH and cigarette smoking in Saudi Arabia [8].As such,

Data analysis
We used IBM SPSS Statistics, version 26.0 (IBM Corp., Armonk, NY) for data analysis.To present the categorical data, we used frequencies and percentages, whereas numerical variables were expressed as median and interquartile ranges (IQRs).Fisher's exact test or Pearson's chi-squared test was used to test for the association between AIH and the factors that cause complications.Fisher's test was used to determine whether the proportion of the data collected by two or more categorical variables is randomized.The chisquared test compares the expected results and the observed results and determines whether the difference between them is due to variables that we are studying or by chance.The statistical significance was considered at p < 0.05.

Results
More than one-third of the patients (39.1%; n = 18) had an age ranging from 18 to <40 years, and less than two-thirds of them (63.0%;n = 29) were females.Five (10.9%) patients were active smokers; of them, three (60.0%)used cigarettes, one (20.0%)used shisha, and one (20.0%)used e-cigarettes.The median (IQR) number of cigarettes smoked per day was 17.0 (13.5, 18.5).Rather than those active smokers, five (10.9%) patients were ex-smokers, and all of them had used cigarettes.
The development of any complications was not associated with patients' gender, age, or receiving over-thecounter medications.Additionally, the smoking status was not associated with the development of any complications (Tables 3, 4).

TABLE 4: Assessment of factors associated with the incidence of cirrhosis or esophageal varices as complications due to autoimmune hepatitis
Liver cirrhosis development was significantly higher among currently active smokers (36.4% vs 2.9%, p = 0.009).A larger proportion of patients who developed esophageal varices were using over-the-counter medications (50.0%vs 4.8%, p = 0.033), yet the complication was not associated with the smoking variables (Table 4).

Discussion
This study aimed to assess the relationship between cigarette smoking and AIH outcomes.Research analysis and results indicated that there was no association between cigarette smoking and AIH outcomes.
The current study found that 39.1% (n = 18) of the patients had at least one complication of AIH, with liver cirrhosis being the most common.Furthermore, the presence of any complication was unrelated to the patient's demographics or smoking status.However, the prevalence of liver cirrhosis was significantly higher among current smokers.The current study's findings are consistent with previous research, which found that 35% of AIH patients had liver cirrhosis.Furthermore, Wong et al. reported that 33.9% of 183 patients with AIH in their study had liver cirrhosis [9].This finding was supported by another study examining the epidemiology of AIH in the United States [10].
Although the biological pathway by which cigarette smoking increases the prevalence of autoimmune phenomena is not fully understood, several potential mechanisms have been proposed.Cigarette smoke may cause the release of intracellular antigens via tissue hypoxia or toxin-mediated cellular necrosis, thereby overwhelming the immune system's scavenging capacity and precipitating an immune reaction in susceptible individuals.Byproducts of cigarette smoking can boost auto-reactive B cells [11].Cigarette smoke contains a polyphenol-rich glycoprotein isolated from tobacco leaves.It has been shown to stimulate peripheral T-lymphocyte proliferation [12].
Cigarette smoke contains extremely high levels of free radicals.It can also increase the production and activation of endogenous free radicals.These toxins interact with DNA, causing genetic mutations and gene activation, which can lead to autoimmune diseases [13].
Even though liver cirrhosis was seen among active smokers, it is inconclusive that the AIH outcome was due to smoking.In 2021, a prospective cohort study conducted in the USA reported that the correlation between smoking and AIH remains questionable [14].
Several studies have shown an association between cigarette smoking and the development of complications of other autoimmune diseases, but there isn't any study done on AIH [5][6][7].The results also showed that there is no relationship between the development of AIH outcomes and the age, gender, or receiving over-the-counter medication.It was seen among the patients who developed esophageal varices and were taking over-the-counter medication.The important result of the present study was the higher prevalence of liver cirrhosis among currently active smokers (36.4% vs 2.9%, p = 0.009).Previous studies revealed that smoking was significantly associated with the development of non-alcoholic fatty liver disease (NAFLD) and NAFLD-cirrhosis compared to those without [15].At the same time, other studies found an association between cigarette smoking and the progression of fibrosis in chronic liver diseases [16].
A population cohort study discovered a direct link between smoking and liver cirrhosis.This study discovered that among those who smoked 10 or more grams of tobacco per day, women had a hazard ratio of 2.2 (1.4-3.4) for liver cirrhosis, and men had a hazard ratio of 1.4 (0.9-2.2) for liver cirrhosis after adjusting for alcohol consumption [17].Tobacco use has been linked to 12% of female liver cirrhosis cases and 6% of male liver cirrhosis cases [17].After six years, smoking was predictive of liver disease in a sample of 1,290,413 women [18].
A careful literature search found no adequate articles published to address the association between cigarette smoking and outcomes of AIH.Thus, this makes it difficult to compare our results to other study results.

Limitations
A limitation of the present study was the small sample size and the fact that it was a single-center study, which hindered the generalization of the study results.

Conclusions
This research showed no relationship between cigarette smoking and the development of AIH outcomes.It is challenging to get a full picture or to prove the association between smoking and AIH due to the small population available, and some of them denied having the disease.We might have had a different result if we had conducted this study on a larger population.In addition to the population size, it would be helpful to look into how smoking caused the development of AIH outcomes and if we were able to have before and after data on those who stopped smoking.This will be helpful in studying if any improvements were observed after smoking cessation.In addition to those suggestions to improve the study, we could include other methods to collect data to have a better understanding of the relationship between cigarette smoking and AIH complications.