I. Etiology and pathogenesis
The specific pathogenesis of ALD remains unknown, and most scholars believe that it may be mainly related to cell death and tissue damage. an important cause of ALD progression is the progressive loss of the liver’s ability to produce and provide adequate levels of ATP, and this decrease in capacity is associated with decreased hepatocyte activity, which eventually leads to pathological changes caused by the resulting alcohol hepatotoxicity. Using transfected HepG2 cells (VA-13) overexpressing alcohol dehydrogenase to understand the bioenergetic capacity of hepatocytes, Gyamfi et al. in the UK found that intracellular ATP levels and mitochondrial membrane potential of VA-13 cells in glucose medium decreased significantly over time under alcohol exposure. Among them, the higher the alcohol concentration, the more pronounced was the LDH leakage, accompanied by apoptosis.
In alcoholic steatohepatopathy, the TLR4-dependent pathway activates hypoxia-inducible factor 1α (HIF1α) in hepatocytes, resulting in steatosis. In the later stages of alcoholic liver disease, early growth response protein (EGR)1 is a key transcription factor that promotes not only liver fibrosis but also steatosis development. experiments in the LE rat model suggest that the above effects of EGR1 are dependent on binding to SREBP1 enhancers. Uncontrolled alcohol consumption predisposes to hepatic microvascular steatosis, elevated hepatic triglycerides and aminotransferases, and hepatocyte apoptosis, and these changes are often accompanied by upregulation of pro-inflammatory factors Cxcl1 and Cxcl2 gene expression and hepatic neutrophil infiltration.
Kirpich et al. from USA reported that hepatic steatosis was associated with hepatic impairment, increased acetylation of histone H3 and decreased activity of histone acetylases (HDACs), in which HDAC1, HDAC7, HDAC9, HDAC10 and HDAC11 gene expression is diminished with upregulation of HDAC3. Monocyte chemotactic protein 2 (CCL2) is of interest because of the recruitment of CCL2+ Th-17 cells that induce IL-8-producing neutrophils. Degre et al. in Belgium counted 123 plasma samples and 74 liver tissue biopsies of ALD patients from 2003-2008 and found that CCL2 plasma levels were significantly higher in ALD patients than in the normal population, and its expression levels were associated with patients’ hepatic venous pressure gradient and MELD score, and liver tissue CCL2 mRNA levels were associated with liver tissue IL-17+ cell infiltration and IL-8 expression. Compared with other ALD patients, the survival rate was significantly lower in AH with higher CCL2 plasma concentration (P25. Alcoholic fatty liver disease (AFLD) was also associated with CAD coronary artery disease, as reported by Choi et al. in Korea.
When treating severe alcoholic hepatitis with adrenocorticosteroids, short-term survival of patients is related to their response to hormone therapy, but the factors influencing long-term survival are inconclusive, and studies on the complex mechanisms of long-term survival are actually more helpful in adopting various short-term or long-term management strategies to improve survival. Louvet et al. in France observed 272 patients with severe alcoholic hepatitis and divided them into responding and non-responding groups according to their response to hormones, with no differences in clinical parameters (gender, AST, alcohol consumption, ascites, hepatic encephalopathy, etc.) between the groups, and survival rates of (87.7±3.0)% and (27.6±4.8)% in the two groups after 6 months, respectively. During follow-up, 53.6% of patients returned to drinking around 180 d. Survival rates were significantly higher in patients who did not return to drinking at 5 years than in those who did [(75.9±6.7)% versus (32.6±8)%], and 87.5% of deaths among those who returned to drinking were associated with complications of cirrhosis. louvet also found that among patients who responded to hormones, 5-year survival rates were higher in those who did not return to drinking than in (80.4±6.8)% versus (39±9)%, P=0.003], and none of the hormone-non-responders survived more than 5 years after drinking again. Thus an important survival factor for patients with severe alcoholic hepatitis in the first 6 months is the effectiveness of hormonal treatment for liver damage, after which the important survival factor is the prohibition of alcohol consumption by the patient.
Mortality is increased in patients with severe AH who do not respond well to adrenal corticosteroids, mainly due to gastrointestinal bleeding and hepatorenal syndrome (HRS). It has been shown that hepatic venous pressure gradient (HVPG) is a predictor of GI bleeding and HRS in cirrhosis. A prospective study by Louvet et al. in France showed that HVPG had no effect on GI bleeding and 6-month survival and was neither predictive of GI bleeding nor related to survival indicators.
Acute kidney injury (AKI) needs to be avoided in AH patients, and SIRS, INR, and blood bilirubin levels are all independent correlates of AKI progression. Multivariate analysis also confirmed that progression of AKI independently predicted 90 d mortality. One study suggested that MDA-HAS (malondialdehyde endocytic albumin) and Cyp2E1 (cytochrome P450 2E1)-responsive antibodies were significantly associated with the risk of mortality. Ceramide with cytotoxic properties can lead to IR and hepatic lipotoxicity, thus the degree of ceramide accumulation affects ALD progression. Irish Setshedi et al. suggested that the degree of hepatic steatosis, hepatocytotoxicity and mitochondrial dysfunction could be reduced by inhibiting ceramide synthesis in adult male rats with LE using chemical inhibitors, insulin sensitizers, and antioxidants (PPAR antagonists).
In addition, genotype is one of the factors affecting prognosis. The PNPLA3 genotype was found to be a potential predictor of ALD in European Caucasian whites by Trepo et al. The C/G rs738409 PNPLA3 genotype was more frequent in ALD patients. People with this genotype were more likely to develop fatty liver, liver fibrosis and cirrhosis compared to the normal population. Multivariate analysis also confirmed that C/G rs738409 PNPLA3 was independently associated with cirrhosis (P=0.002).
II. Coexisting viral hepatitis
Acute alcoholic hepatitis (AHH) has a high mortality rate. In Europe and the United States, alcohol abuse and viral hepatitis C (HCV) often coexist, but little is known about the impact of HCV on AHH. Singal et al. in the United States investigated the 2007 public hospital inpatient data and concluded that HCV infection was a predictor of severe AHH, affecting not only hospitalization but also long-term prognosis. Thuluvath et al. studied the national data of inpatients with alcoholic hepatitis (AH) from 1998 to 2006 (20% were emergency admissions, excluding patients with cirrhosis) and found that a total of 22,902 patients were diagnosed with AH, of whom 1,398 had HCV in combination, 1,459 had developed hepatic encephalopathy, with an in-hospital mortality rate of 3.3% and 19% died of hepatic encephalopathy. Patients with comorbid HCV tend to be younger, have lower economic income, and have a higher mortality rate compared to patients with AH alone. Independent associations between HCV and AH were determined using statistical regression, and additional influencing factors were hepatic encephalopathy, age, malnutrition, and Charlson index in that order according to the correlation.
HCV alone has a very limited effect on the liver, as only 7% to 20% of hepatocytes can be infected by the virus in general. Alcohol intake has been shown to exacerbate HCV infection. Osna et al. in Nebraska suggested that alcohol-induced HCV transmission is regulated by the oxidative stress pathway by the following mechanisms, following induction by alcohol exposure
(1) HCV transmission to uninfected neighboring cells through diffusion, which enhances intracellular accumulation of HCV core protein and becomes another source of oxidative stress;
(2) further exacerbates HCV infection by oxidative stress-mediated damage to the interferon IFNα pathway. On the basis of chronic alcohol exposure, the mechanism of HCV pathogenesis is related to FOXO3 transcriptional activity, which regulates SOD2 levels and cytotoxicity through alterations in FOXO3 transcriptional activity, thereby causing liver damage.Tumurbaatar et al. stably transfected Huh7.5 cells to CYP2E1 and divided them into control and infected groups (infected with HCV) and found that in the control group FOXO3 was mainly present in the nucleus, and after HCV infection FOXO3 gradually moved to the cytoplasm, and the stability of FOXO3 protein was reduced, and the expression of its target genes SOD2 and BIM was also decreased. In the control group, alcohol had little effect on FOXO3 and its target genes, whereas in the infected group, alcohol up-regulated its expression and then down-regulated this expression. Therefore, the altered transcriptional activity of FOXO3 was due to the combined effect of alcohol and HCV.
III. Use of various integral methods
Currently, the commonly used integral models for patients with alcoholic liver disease include ABIC, Glasgow, Lille, Maddrey and MELD, etc. The use of these integral methods is useful for the adjustment of clinical treatment strategies, among which the Maddrey integral method is commonly used to predict short-term mortality in patients with AH, and the Lille integral formula incorporates the efficacy after 7 d of treatment. Louvel et al. in France prospectively studied 332 patients with severe AH (Maddrey>=32) to select an appropriate integral model to predict treatment efficacy and assess 6-month survival. These patients were 55.9% male, 74.2% ascites, 24.3% hepatic encephalopathy, 50.5 years of age, 100 g/d alcohol consumption, PT 20.9 s, INR 1.9, AST 109 IU/L, albumin 25 g/L, bilirubin 15.6 mg/dL, creatinine 0.86 mg/dL, and were given 40 mg/d prednisolone, while recording separately The values of each score after 1 d and 7 d of treatment were recorded, and it was found that the ABIC and MELD scores were more suitable for the assessment of clinical symptoms, while the Lille score was more accurate in predicting the effect of treatment after 6 months.
Louvet et al. in France treated 641 patients with alcoholic hepatitis with adrenocorticosteroids according to the recommendations of the American guidelines. the mean value of the Lille score of these enrolled patients was 0.29, and the patients were divided into three groups according to their response to the hormone: the completely effective group (0.56), with no differences in clinical parameters (gender, AST, alcohol consumption, ascites, hepatic encephalopathy, etc.) among the three groups. the survival rates of the three groups after 6 months were The survival rates of the three groups after 6 months were (87.7±2.3)%, (69.5±3.3)% and (20.8±3.1)%, respectively, with death occurring significantly earlier in the null group. Clinical results confirmed that the fully effective group (Lille score 0.56) was at high risk of death, and this group of patients should be treated as early as possible with liver transplantation.
For patients with chronic liver failure in cirrhosis, we commonly use the Child-Pugh-Tcotte classification or the MELD score to evaluate their liver function, which are dependent on liver enzymes, lactate, lipid and glucose metabolism and other organ functions and do not provide predictors. By analyzing 169 hospitalized patients suffering from alcoholic liver disease, Amathieu et al. in France proposed to understand their glucolipid metabolism by serum proton NMR spectroscopy to assess the degree of chronic liver failure in patients with alcoholic liver disease and cirrhosis.
IV. Treatment
Enteric-derived endotoxins promote increased inflammatory cytokines such as TNFα and play an important role in alcoholic liver disease. An earlier study by Ambade et al. in Massachusetts found that in hepatic macrophages, chronic alcohol exposure caused LPS-induced high expression of Hsp90 mRNA and protein. hsp90 is known as a chaperone molecule of alcoholic liver damage, and its inhibitors function to inhibit LPS-induced production of TNFα. ambade et al. showed that by using an HSP90 inhibitor (geldanamycin derivative, 17 -DMAG) successfully downregulated CD14 mRNA expression induced by LPS in hepatocytes while attenuating macrophage TNFα agonist activity. Therefore, they suggested that 17-DMAG could be applied as an HSP90 inhibitor to attenuate alcoholic liver function impairment produced by LPS.
Ki et al. in the USA found increased expression of IL-22R1 in liver tissue of alcohol-fed rats or in patients with alcoholic hepatitis, where IL-22 was not measurable, and hepatic STAT3 gene activation and improved liver function with no adverse effects were observed after administration of IL-22 addition. Further studies have confirmed that IL-22 belongs to the IL-10 family of cytokines, which are produced by Th17 and NK cells. It not only down-regulates the expression of fatty acid transport proteins in hepatocytes, but also up-regulates antioxidant factors, anti-apoptotic genes and anti-bacterial genes, and therefore has an important role in the control of bacterial infection, hormone regulation and tissue repair, and can be used as a potential treatment for alcoholic liver disease.
V. Others
Small or appropriate alcohol consumption may reduce the incidence of cardiovascular events and reduce the risk of diabetes progression. Hiramine et al. in Japan even suggested that alcohol is a protective factor for liver disease and that appropriate alcohol consumption can prevent fatty liver (FL).