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. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: Pancreatology. 2020 Jul 30;20(6):1069–1077. doi: 10.1016/j.pan.2020.07.412

Coexistence of Alcohol-related Pancreatitis and Alcohol-related Liver Disease: A systematic review and meta-analysis

Ajay Singhvi 1, Rebecca Abromitis 2, Andrew D Althouse 3, Ramon Bataller 4, Gavin E Arteel 5, Dhiraj Yadav 6
PMCID: PMC7970449  NIHMSID: NIHMS1622352  PMID: 32800649

Abstract

Background:

Available estimates of coexistent alcohol-related pancreatitis (ALP) and alcohol-related liver disease (ALD) vary widely, and factors that determine coexistent disease are largely unknown. We performed a systematic review of published literature with the primary aim to generate robust estimates for coexistent alcohol-related chronic pancreatitis (ACP) and alcohol-related cirrhosis (ALC).

Methods:

We searched PubMed, EMBASE, and Web of Science databases from inception until 2/2018. Studies included were those in English-language, sample size ≥25 and allowed calculation of the coexistent disease. Pooled estimates were calculated using a random-effects model approach.

Results:

Twenty-nine (including 5 autopsy studies) of 2000 eligible studies met inclusion criteria. Only 6.9% included patients were female. Fifteen studies enabled calculation of ACP in ALC, and 11 for ALC in ACP. Pooled prevalence of ACP in ALC was 16.2% (95% CI 10.4–24.5) overall, and 15.5% (95% CI 8.0–27.7) when data were limited to clinical studies. Corresponding prevalence for ALC in ACP was 21.5% (95% CI 12.0–35.6) and 16.9% (95% CI 11.5–24.3), respectively. There was significant heterogeneity among studies (I2 – 65–92%). Pooled prevalence for ALP in ALD or ALD in ALP in clinical studies were 15.2% and 39%, respectively. None of the studies reported outcomes in patients with coexistent disease.

Conclusion:

A sizeable fraction of patients with ACP or ALC have coexistent disease. Future studies should define the prevalence of coexistent disease in women and minority populations, and the consequences of coexistent disease on clinical presentation and short- and long-term outcomes.

INTRODUCTION

It is reported that 88% of U.S. adults have consumed alcohol at some point in their lives (1). Alcohol use disorders affect approximately 15.1 million US adults. Alcohol abuse has been linked to a number of detrimental health effects. Its manifestations can involve many organs and present with a variety of phenotypes, and alcohol is known to contribute to roughly 200 disease states (2). Ultimately, alcohol consumption is responsible for ~6% of all disability-adjusted life years (DALYs) lost in the United States (3), most of which are attributable to end-organ damage as opposed to alcohol-related accidents. Two digestive organs that are commonly injured by excessive alcohol consumption are the liver and pancreas (4, 5).

Manifestations of alcohol-related liver disease (ALD) include alcohol-related fatty liver (AFLD), alcohol-related hepatitis (AH) and alcohol-related cirrhosis (ALC), while for alcohol-related pancreatitis (ALP) include acute alcohol-related (AAP) and alcohol-related chronic pancreatitis (ACP). Only a small fraction of patients with alcohol-use disorder develops these diseases (5–7). Individual susceptibility to ALD and ALP is primarily determined by the amount and length of alcohol consumption, but is modified by factors, such as race, other environmental factors and genetic variation (8–13). The concentrations of alcohol found in the portal blood are much higher than those in the systemic circulation (14). As the liver is the primary site of alcohol metabolism, which produces many toxic metabolites, it is unsurprising that the liver is a primary target of alcohol toxicity. In addition to metabolic stress caused directly by alcohol metabolism, ALD is characterized by low-grade hepatic inflammation that is incompletely compensated by regeneration (15). Alcohol also affects the pancreas both directly and indirectly. In addition to metabolic load, alcohol appears to alter the inflammatory response to a secondary insult (16). As in liver, the chronic low-grade inflammation in ALP eventually transitions to a maladaptive fibrotic response (17, 18).

Each of these primary alcohol-related diseases is associated with short- and long-term consequences for an individual. Consequences of ALC include portosystemic encephalopathy, gastrointestinal bleeding, and infection (19), while ACP is associated with acute pancreatitis, exocrine and endocrine insufficiency, and local complications such as pancreatic necrosis, pancreatic fluid collections, gastric varices, and pseudoaneurysm (20). Both conditions can be associated with malignancies, i.e. hepatocellular carcinoma (21, 22) and pancreatic ductal adenocarcinoma (23), respectively. Life-expectancy in patients with ALC and ACP is significantly lower when compared with background population (24–26).

Coexistence of ALD and ALP is sometimes seen in clinical practice - estimates vary widely in the literature, ranging from 1.4 – 70% (27–37) for prevalence of ACP in ALC, and from 0.0–74.7% (31, 32, 38–41) for prevalence of ALC in ACP. Due to high variability, a better understanding of the true overlap between these diseases is necessary. Moreover, given the significant impact of ALD and ALP individually, it is likely that patients with both ALC and ALP will have poorer outcomes when compared with those with either disease alone. Our primary goal was to determine robust prevalence estimates of coexistent severe ALD (ALC) and severe ALP (ACP) by conducting a systematic review of the published literature. Our secondary aim was to investigate the coexistence of any ALD (AFLD, AH, ALC) and ALP (AAP or ACP).

METHODS

This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

Data Sources and Searches

Using an iterative process between study investigators (A.S., D.Y.) and a medical librarian (R.A.), we developed search strategies using controlled vocabulary and text words appropriately adapted for each of these databases: PubMed (1946–2018), EMBASE (1974–2018), and Web of Science (1945–2018). Our strategy was to conduct a broad search by combining four concepts: alcohol-related liver diseases, pancreatitis, alcohol use, and prevalence, incidence or risk factors. All searches were conducted, and records downloaded between May and August 2018, and search results subsequently filtered to English language studies published from 1965 and 2018.

Study Selection

Articles identified from the search were imported into an EndNote library (Thompson Reuters, X7). Identified abstracts were retained by one investigator (A.S.) if they allowed calculation of the prevalence of coexistent disease for ALP in ALD or ALD in ALP and had sample size ≥25. Abstracts and letters to the editor without a full manuscript that detailed the methods of the study were excluded. Non-English studies, reviews, experimental studies using animal models, and duplicate publications were also excluded. The studies finally included in this review were autopsy and cross-sectional studies. When uncertainty occurred regarding an article’s inclusion/exclusion, a second investigator (D.Y.) was asked to review the said article to help determine inclusion. This discussion always led to a consensus decision whether to include or exclude the article.

Data Extraction

The following information was collected by A.S.: study design, year of publication, country of study, the number of cases to allow for prevalence data calculation stratified by gender, if available, mean age +/− SD, and modality used to define acute pancreatitis, chronic pancreatitis, ALP, ALD, and ALC. Information was collected systematically from each study using a predefined data collection form.

Data Synthesis and Analysis

Prevalence for each of the individual studies was computed by dividing frequency of each respective condition within the other condition of interest (e.g. 42 patients with ALP out of 390 patients with ALD = 10.8% in Agrawal 2014 (42)). Pooled prevalence estimates for each combination for the disease of interest were calculated using a random-effects model with the DerSimonian and Laird variance estimator. All point estimates are presented with 95% confidence intervals. Sensitivity analyses were performed after exclusion of autopsy studies. All statistical analyses were performed in R version 3.4.1 using the “meta” package (43).

RESULTS

Study Selection and Study Characteristics.

The flowchart of the systematic review is depicted in Figure 1. Of the 2,000 articles screened, 32 articles fit the criteria for review. Of these, 3 articles were excluded after further review. One only reported prevalence calculations of ALC in ACP, but did so from a subgroup analysis of patients with ACP that had died during follow-up (44). Another was excluded because prevalence were reported based on an administrative dataset using ICD-9 codes for discharge diagnoses; but the study could not identify unique patients with such diagnoses resulting in the possibility of repetitive counts of a single patient (45). One article was excluded due to the lack of full text availability (46). The remaining 29 articles selected for the final analysis (27–42, 47–59) (Table 1).

Figure 1:

Figure 1:

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Literature flow diagram.

Table 1:

Overview of characteristics of studies included in this systematic review and meta-analysis

First Author of Study Year of publication Country Primary Focus of the Study Total Sample Size Age (mean) Males (%) Criteria used for diagnosing ACP or ALP Criteria used for diagnosing ALC or ALD
ACP in ALC ALC in ACP ALP in ALD ALD in ALP ALD in ACP ACP in ALD ALP in ALC ALC in ALP
Adams et al* 1980 United States X X X X 126 53 74% Pathology Pathology
Agrawal et al* 2014 India X X X X 390 45 100% Pathology Pathology
Martin et al* 1989 France X X 148 58 66% Pathology Pathology
Pace et al* 2009 Germany X X X X X X X X 585 54 73% Pathology Pathology
Renner et al* 1984 United States X X X X 1022 53 - Pathology Pathology
Buchner et al 2001 United States X X 40906 55 99% Diagnosis Code Diagnosis Code
Chedid et al 1986 United States X 220 - - Diagnosis Code Pathology
Darstein et al 2014 Germany X 147 55 - CT, MRI, EUS, ERCP, Diagnosis Code -
Montalto et al 1992 France X X 121 43 88% Pathology, ERCP, Functional Testing Pathology
Nguyen et al 2016 United States X 6113 48 69% - Diagnosis Code
Soni et al 2015 India X 95 39 100% CT, MRI, ERCP Ultrasound
Wehmeyer et al 2017 Germany X 222 - - CT, MRI, ERCP Diagnosis Code
Aoufi et al 2014 Spain X 125 53 95% EUS Clinical diagnosis
Aparisi et al 2008 Spain X X 110 52 (for CP); 56 (for cirrhosis) 91% ERCP, functional testing Clinical diagnosis
Caradonna et al 1996 Italy X 35 59 71% ERCP Pathology, Labs
Chebli et al 1997 Brazil X X 32 35 100% CT, ERCP Pathology
Davis et al 1969 Australia X X 25 - - Functional Testing Pathology
Dutta et al 1978 United States X X X X 50 47 100% Pathology, MRI, ERCP Pathology, Labs
Frossard et al 2013 Switzerland X 28 49 - CT, EUS Pathology
Gullo et al 1995 Italy X X 50 46 88% Pathology Pathology
Hastier et al 1999 France X 72 56 53% EUS, ERCP Pathology, CT, MRI
Hayakawa et al 1991 Japan X X X X 71 43 94% ERCP Pathology
Hietanen et al 2014 Finland X 50 49 - - Elastography
Jalleh et al 1991 England X X 40 41 - Pathology Pathology
Kochhar et al 2003 India X X 46 44 100% ERCP Pathology, Ultrasound, CT
Lesur et al 1993 France X X 48 42 96% CT, ERCP Pathology
Otete et al 2016 England X 2479 56 67% Diagnosis Code Diagnosis Code
Spicak et al 2012 Czech Republic X X 146 48 (for CP); 37 (for cirrhosis) 85% CT, MRI, EUS, ERCP Pathology
Testoni et al 1984 Italy X X 35 - 71% ERCP Pathology
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A total of 13 countries were represented in these 29 studies - the majority of the articles were from Europe (59%), North America (21%), and Asia (10%). Roughly 50% of the studies were published after year 2000. Five of the studies were based on autopsy data (31, 36, 38, 42, 51) (Table 1). Mean age ranged from 35.0 to 58.6 years. Women were included in 21 studies, and the proportion of women ranged from 0–47.2%. Of 51,783 subjects, only 3462 (6.9%) were female (Table 1). Among US studies, breakdown for minority populations was not provided. Among these data, more subjects were available to assess the prevalence of ACP in ALC (n=2,211 from 15 studies) than to calculate the prevalence of ALC in ACP (n=652 from 11 studies). Similarly, more subjects were available to assess the prevalence of ALP in ALD (n=49,292 from 7 studies) than to calculate the prevalence of ALD in ALP (n=456 from 3 studies). Criteria used for diagnosing ACP, ALP, ALC, and ALD in each study are detailed in Table 1.

Synthesis of Results

ACP in ALC

A total of 15 studies were identified that enabled for a prevalence calculation for ACP in ALC, 5 of which were autopsy studies. The number of cases of ACP were 373 among 2,211 cases with ALC. This resulted in a pooled prevalence of ACP in ALC to be 16.2% (95% CI 10.4–24.5) (Figure 2), with an I2 = 92% suggesting high heterogeneity. One autopsy study (51) contributed heavily to this analysis, comprising 783 out of the 2,211 ALC patients. Removal of this study resulted in a pooled prevalence estimate of 15.3% (95% CI 8.5–25.8). After excluding all five of the autopsy studies, the prevalence estimate for ACP in patients with ALC decreased to 15.5% (95% CI 8.0–27.7) with high heterogeneity among the studies (I2 = 87%) (Figure 3). Limiting the analysis to only the five autopsy studies yielded a prevalence of ACP of 16.9% (95% CI 8.0–32.3%) among patients with ALC.

Figure 2:

Figure 2:

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Forest plot depicting the prevalence of alcohol-related chronic pancreatitis in alcohol-related cirrhosis. CI (Confidence Intervals).

Figure 3:

Figure 3:

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Forest plot depicting the prevalence of alcohol-related chronic pancreatitis in alcohol-related cirrhosis after removal of autopsy studies. CI (Confidence Intervals).

ALC in ACP

A total of 11 studies were identified that enabled for a prevalence calculation for ALC in ACP, 2 of which were autopsy studies. The number of cases of ALC were 171 among 652 cases of ACP. This resulted in a pooled prevalence of ALC in ACP to be 21.5% (95% CI 12.0–35.6), (Figure 4) with high heterogeneity (I2 = 91%). After excluding autopsy studies, the pooled prevalence of ALC in ACP decreased to 16.9% (95% CI 11.5–24.3) (Figure 5), again with high heterogeneity (I2 = 65%). Limiting the analysis only to the two autopsy studies increased the pooled prevalence greatly to 57.7% (95% CI 23.2–86.0).

Figure 4:

Figure 4:

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Forest plot depicting the prevalence of alcohol-related cirrhosis in alcohol-related chronic pancreatitis. CI (Confidence Intervals).

Figure 5:

Figure 5:

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Forest plot depicting the prevalence of alcohol-related cirrhosis in alcohol-related chronic pancreatitis after removal of autopsy studies. CI (Confidence Intervals).

Any ALP in any ALD

A total of 7 studies were identified that enabled for a prevalence calculation for ALP in ALD, 3 of which were autopsy studies. The number of cases of ALP were 8,003 among 49,292 cases of ALD. This resulted in a pooled prevalence of ALP in ALD to be 19.7% (95% CI 13.5–27.7) with a high heterogeneity (I2 = 99%). One administrative data study (48) contributed heavily to the initial analysis, comprising 40,906 out of the 49,262 subjects with ALD. Removal of this single study had only a small effect on the pooled prevalence of ALP which was 20.1% (95% CI 10.1–35.8). After excluding autopsy studies, the pooled prevalence decreased to 15.2% (95% CI 14.3–16.1) in the remaining four clinical studies. Limiting the analysis only to autopsy studies resulted in a pooled prevalence of ALP to be 29.3% (95% CI 11.0–58.2) among cases with ALD.

Any ALD in Any ALP

A total of 3 studies were identified that enabled for a prevalence calculation for ALD in ALP, one of which was an autopsy study. The number of cases of ALD were 390 among 456 cases with ALP. This resulted in a pooled prevalence of ALD to be 67.8% (95% CI 16.0–95.9) among cases with ALP (I2 = 98%). After excluding the one autopsy study, the pooled prevalence decreased to 39.0% (95% CI 30.0–48.9).

ALP in ALC

A total of 8 studies were identified that enabled for a prevalence calculation for ALP in ALC, three of which was were autopsy studies. The number of cases of ALP were 2,956 among 21,897 cases of ALC. This resulted in a pooled prevalence of ALP to be 22.1% (95% CI 11.7–37.7) in ALC, with high heterogeneity (I2 = 99%). One large administrative study (48) contributed heavily to the initial analysis, comprising 17,881 out of the 21,897 total subjects with ALC. Removal of this single study resulted in a pooled prevalence of ALP to be 23.5% (95% CI 8.5–50.3) in ALC. After excluding autopsy studies, the pooled prevalence of ALP in ALC decreased to 7.9% (95% CI 2.5–22.6). Limiting the analysis only to autopsy studies resulted in a pooled prevalence of ALP to be 35.7% (95% CI 16.9–60.1) in cases with ALC.

The coexistence for other combinations is shown in Tables 1 and 2.

Table 2:

Summary of pooled estimates of coexisting ALP and ALD

Group Prevalence of Interest Study selection Pooled prevalence (95% CI)
ALC ACP All studies (n = 15)
Clinical studies (n = 10)
Autopsy studies (n = 5)		 16.2 (10.4 – 24.5)
15.5 (8.0 – 27.7)
16.9 (8.0 – 32.3)
ALC ALP All studies (n = 8)
Clinical studies (n = 3)
Autopsy studies (n = 5)		 22.1 (11.7 – 37.7)
7.9 (2.5 – 22.6)
35.7 (16.9 – 60. 1)
ALD ACP All studies (n = 7)
Clinical studies (n = 4)
Autopsy studies (n = 3)		 19.8 (13.1 – 28.7)
27.1 (13.5 – 46.9)
13.6 (8.6–21.0)
ALD ALP All studies (n = 7)
Clinical studies (n = 4)
Autopsy studies (n = 3)		 19.7 (13.5 – 27.7)
15.2 (14.3 – 16.1)
29.3 (11.0 – 58.2)
ACP ALC All studies (n = 11)
Clinical studies (n = 9)
Autopsy studies (n = 2)		 21.5 (12.0 – 35.6)
16.9 (11.5 – 24.3)
57.7 (23.2 – 86.0)
ACP ALD All studies (n = 9)
Clinical studies (n = 7)
Autopsy studies (n = 2)		 49.3 (29.4 – 69.4)
35.8 (19.3 – 56.6)
88.0 (52.7–98.0)
ALP ALC All studies (n = 2)
Clinical studies (n = 1)
Autopsy studies (n = 1)		 36.6 (30.0 – 43.9)
30.0 (17.9 – 44.6)
38.5 (33.4 – 43.8)
ALP ALD All studies (n = 3)
Clinical studies (n = 2)
Autopsy studies (n = 1)		 67.8 (16.0 – 95.9)
39.0 (30.0 – 48.9)
95.8 (93.1 – 97.6)
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DISCUSSION

In this systematic review, we report pooled estimates of coexistent ALD and ALP based on published literature. We note that about one in 6 patients with ACP have clinical evidence of ALC, and a similar fraction of ALC patients have clinical evidence of ACP. About one in five patients with ALD had ALP, while a much greater proportion (~40%) of ALP patients had ALD. The prevalence of coexistent disease was greater in studies limited to autopsy material. We provide a context to interpret these data, including reasons for variability in estimates, and highlight the paucity of data in women and minority populations.

Only a subset of individuals who abuse alcohol develop ALD or ALP (5–7). Often in clinical practice, patients who have evidence of disease in both organs are encountered. How often does coexistent disease occurs was the primary focus of our study. Many investigators have attempted to define the prevalence of coexistent ALP and ALD. However, the estimates vary greatly between studies due to differences in study design, time period of study, geographic location of the study, and diagnostic criteria used. Studies also differed in the type of coexisting disease evaluated, e.g. evaluation of ALD vs. ALC and ALP vs. ACP. Identifying coexistent disease depends on many factors – of these, diagnostic criteria utilized are likely the most important. Clinical presentation, laboratory testing, cross-sectional imaging, and administrative datasets each have limitations in sensitivity and specificity, while pathologic diagnosis is likely the most accurate. However, pathology is often not available, especially in patients with ALP. Limitations of pathology include patchy disease, which may lead to sampling error (60). Other factors of importance include geographic variability due to the distribution of risk factors, i.e. exposure to alcohol, and time period of study which would impact the type of tests used for diagnosis, e.g. increasing use of endoscopic ultrasound and MRI/MRCP to diagnose chronic pancreatitis (61, 62). Our systematic review provides robust estimates of the coexistence of these diseases based on available data. It is important to highlight that few women were included in the studies, and although data are available from different continents, certain population groups, e.g. Blacks, Hispanics, American-Indians, etc. were under-represented.

The pooled prevalence of coexistent disease was greater in studies focusing on the use of autopsy material (31, 36, 38, 42, 51). This is not surprising as pathology is more likely to identify the presence of subclinical disease that would not otherwise be identified based on clinical symptoms or radiographic findings. How often does this diagnosis lead to clinical symptomatology is not adequately answered by the studies included in our analyses or in the literature. We believe that the true prevalence of coexistent disease likely lies somewhere in between the clinical and autopsy estimates of our analyses.

In addition to the amount of alcohol consumption, individual susceptibility to ALD or ALP has been attributed to other environmental and genetic factors (8–13). Of the studies reviewed in this systematic review, none assessed or speculated as to which factors may predict coexistent disease.

The liver and the pancreas are related developmentally and exhibit a number of structural and functional similarities. Furthermore, alcohol-induced damage in these organs exhibit some common features. The diseases in both organs are characterized by parenchymal cell damage, activation of resident stellate cells, and subsequent fibrosis (63). There are several pathogenic reasons that may contribute to the high prevalence of coincidence of ALC and ACP. First, both organs are particularly susceptible to common consequences of alcohol toxicity including acetaldehyde adducts, oxidative stress and increased circulating lipopolysaccharides (64). Second, the development of ACP could influence the progression and clinical decompensation of underlying ALD. Patients with ALD have high prevalence of pancreatic exocrine insufficiency. The resulting abnormal absorption of nutrients and vitamins such as vitamin D could in turn exacerbate liver fibrosis in patients with ALD (47, 65). Moreover, CP can cause and possibly exacerbate portal hypertension, favoring related complications such as variceal bleeding (66, 67). Likewise, the existence of underlying ALC could exacerbate the clinical course of ACP. Third, alcohol-induced fatty liver and the resulting increase in circulating fatty acid ethyl esters may cause multi-organellar dysfunction in the pancreas, which ultimately leads to pancreatitis development (68). ACP and ALC cause short- and long-term consequences in individuals affected by these diseases (20–23). However, there are important questions in patients with coexistent disease that may affect management but remain unanswered. Are subjects with coexistent disease more prone to symptomatology of liver or pancreatic disease? What is the impact of coexistent disease on the clinical course or the overall survival when compared with patients who have clinical disease in only one organ? Unfortunately, these questions have not been answered by the existing studies and should be the focus of future research.

In conclusion, our systematic review calculates the pooled prevalence of clinically apparent ACP among patients with ALC in about 15–20% patients, and a similar fraction of patients with ACP have ALC. About one in five patients with ALD had ALP, while a much greater proportion (~40%) of ALP patients had ALD. The prevalence of coexistent disease was greater in studies limited to autopsy material. Future studies should provide estimates of coexistent disease in women and minority populations, and also focus on the impact of coexistent disease on clinically relevant outcomes.

Acknowledgement:

The authors thank the Collaborative Alliance of Pancreas Education and Research (CAPER) Scholars Program, and the Enhancing MEntoring to Improve Research in GastroEnterology (EMERGE) Program of the Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh for supporting this project.

Funding Sources:

DY (UO1 DK108306, DoD PR 182623); AAD (R01 CA19710 (NIH), W81XWH-15-1-0663 (DoD), R01 CA235730-01 (NIH), U01 GM132133 (NIH), R61 HL144669-01 (NIH), R21 TR003094-01 (NIH), R34 HL132031 - 01A1 (NIH); GEA (R01AA021978 and P30DK120531).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Defense.

Abbreviations:

ALD

Alcohol-related Liver Disease

ALC

Alcohol-related Liver Cirrhosis

ALP

Alcohol-related Pancreatitis

ACP

Alcohol-related Chronic Pancreatitis

Footnotes

The authors declare no relevant conflicts.

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Contributor Information

Ajay Singhvi, Division of Gastroenterology, Hepatology & Nutrition University of Pittsburgh Medical Center Pittsburgh, PA United States.

Rebecca Abromitis, Health Sciences Library System University of Pittsburgh Pittsburgh, PA United States.

Andrew D. Althouse, Division of General Internal Medicine University of Pittsburgh Medical Center Pittsburgh, PA United States.

Ramon Bataller, Division of Gastroenterology, Hepatology & Nutrition University of Pittsburgh Medical Center Pittsburgh, PA United States.

Gavin E. Arteel, Division of Gastroenterology, Hepatology & Nutrition University of Pittsburgh Medical Center Pittsburgh, PA United States.

Dhiraj Yadav, Division of Gastroenterology, Hepatology & Nutrition University of Pittsburgh Medical Center Pittsburgh, PA United States.

REFERENCES

  • 1.Alcohol Use Disorder: U.S. Department of Health and Human Services; [July 21, 2019]. Available from: https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/alcohol-use-disorders.
  • 2.Organization WH. Global Status Report on Alcohol and Health. Poznyak VaR Dag, editor. Geneva, Switzerland: 2018. [Google Scholar]
  • 3.Murray CJ, Atkinson C, Bhalla K, Birbeck G, Burstein R, Chou D, et al. The state of US health, 1990–2010: burden of diseases, injuries, and risk factors. Jama. 2013;310(6):591–608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Rehm J, Taylor B, Mohapatra S, Irving H, Baliunas D, Patra J, et al. Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis. Drug Alcohol Rev. 2010;29(4):437–45. [DOI] [PubMed] [Google Scholar]
  • 5.Samokhvalov AV, Rehm J, Roerecke M. Alcohol Consumption as a Risk Factor for Acute and Chronic Pancreatitis: A Systematic Review and a Series of Meta-analyses. EBioMedicine. 2015;2(12):1996–2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Becker U, Deis A, Sorensen TI, Gronbaek M, Borch-Johnsen K, Muller CF, et al. Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology (Baltimore, Md). 1996;23(5):1025–9. [DOI] [PubMed] [Google Scholar]
  • 7.Irving HM, Samokhvalov AV, Rehm J. Alcohol as a risk factor for pancreatitis. A systematic review and meta-analysis. JOP : Journal of the pancreas. 2009;10(4):387–92. [PMC free article] [PubMed] [Google Scholar]
  • 8.Whitcomb DC, LaRusch J, Krasinskas AM, Klei L, Smith JP, Brand RE, et al. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis. Nat Genet. 2012;44(12):1349–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Zhong Y, Cao J, Zou R, Peng M. Genetic polymorphisms in alcohol dehydrogenase, aldehyde dehydrogenase and alcoholic chronic pancreatitis susceptibility: a meta-analysis. Gastroenterologia y hepatologia. 2015;38(7):417–25. [DOI] [PubMed] [Google Scholar]
  • 10.Buch S, Stickel F, Trepo E, Way M, Herrmann A, Nischalke HD, et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis. Nature genetics. 2015;47(12):1443–8. [DOI] [PubMed] [Google Scholar]
  • 11.Wilcox CM, Sandhu BS, Singh V, Gelrud A, Abberbock JN, Sherman S, et al. Racial Differences in the Clinical Profile, Causes, and Outcome of Chronic Pancreatitis. The American journal of gastroenterology. 2016;111(10):1488–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Aune D, Mahamat-Saleh Y, Norat T, Riboli E. Tobacco smoking and the risk of pancreatitis: A systematic review and meta-analysis of prospective studies. Pancreatology : official journal of the International Association of Pancreatology (IAP) [et al. ]. 2019;19(8):1009–22. [DOI] [PubMed] [Google Scholar]
  • 13.Dam MK, Flensborg-Madsen T, Eliasen M, Becker U, Tolstrup JS. Smoking and risk of liver cirrhosis: a population-based cohort study. Scandinavian journal of gastroenterology. 2013;48(5):585–91. [DOI] [PubMed] [Google Scholar]
  • 14.Utne HE, Winkler K. Hepatic and extrahepatic elimination of ethanol in cirrhosis. With estimates of intrahepatic shunts and Km for ethanol elimination. Scandinavian journal of gastroenterology. 1980;15(3):297–304. [DOI] [PubMed] [Google Scholar]
  • 15.Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, et al. Alcoholic liver disease. Nat Rev Dis Primers. 2018;4(1):16. [DOI] [PubMed] [Google Scholar]
  • 16.Setiawan VW, Monroe K, Lugea A, Yadav D, Pandol S. Uniting Epidemiology and Experimental Disease Models for Alcohol-Related Pancreatic Disease. Alcohol Res. 2017;38(2):173–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nature reviews Gastroenterology & hepatology. 2017;14(7):397–411. [DOI] [PubMed] [Google Scholar]
  • 18.Xue R, Jia K, Wang J, Yang L, Wang Y, Gao L, et al. A Rising Star in Pancreatic Diseases: Pancreatic Stellate Cells. Front Physiol. 2018;9:754. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Jepsen P, Ott P, Andersen PK, Sorensen HT, Vilstrup H. Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study. Hepatology (Baltimore, Md). 2010;51(5):1675–82. [DOI] [PubMed] [Google Scholar]
  • 20.Topazian MG, Fred; Owyang, Chung. Textbook of Gastroenterology - Chapter 95: Chronic Pancreatitis. Yamada T, editor: Lippincott Williams & Wilkins; 2003. [Google Scholar]
  • 21.Alvarez MA, Cirera I, Sola R, Bargallo A, Morillas RM, Planas R. Long-term clinical course of decompensated alcoholic cirrhosis: a prospective study of 165 patients. J Clin Gastroenterol. 2011;45(10):906–11. [DOI] [PubMed] [Google Scholar]
  • 22.Welzel TM, Graubard BI, Quraishi S, Zeuzem S, Davila JA, El-Serag HB, et al. Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. The American journal of gastroenterology. 2013;108(8):1314–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med. 1993;328(20):1433–7. [DOI] [PubMed] [Google Scholar]
  • 24.Yadav D, Timmons L, Benson JT, Dierkhising RA, Chari ST. Incidence, prevalence, and survival of chronic pancreatitis: a population-based study. The American journal of gastroenterology. 2011;106(12):2192–9. [DOI] [PubMed] [Google Scholar]
  • 25.Nojgaard C, Bendtsen F, Becker U, Andersen JR, Holst C, Matzen P. Danish patients with chronic pancreatitis have a four-fold higher mortality rate than the Danish population. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2010;8(4):384–90. [DOI] [PubMed] [Google Scholar]
  • 26.Sorensen HT, Thulstrup AM, Mellemkjar L, Jepsen P, Christensen E, Olsen JH, et al. Long-term survival and cause-specific mortality in patients with cirrhosis of the liver: a nationwide cohort study in Denmark. J Clin Epidemiol. 2003;56(1):88–93. [DOI] [PubMed] [Google Scholar]
  • 27.Caradonna P, Costamagna G, Benedetti G, Gentiloni N, Gasbarrini GB. Chronic pancreatitis prevalence in liver cirrhosis. Morphological and functional study. The Italian journal of gastroenterology. 1996;28(2):91–4. [PubMed] [Google Scholar]
  • 28.Davis AE. Pancreatic function in alcoholic liver disease. The Medical journal of Australia. 1969;1(10):508–9. [DOI] [PubMed] [Google Scholar]
  • 29.Testoni PA, Masci E, Passaretti S, Guslandi M, Tittobello A. Early detection of pancreatic lesions in chronic alcoholism: diagnostic accuracy of ERP. Journal of clinical gastroenterology. 1984;6(6):519–23. [DOI] [PubMed] [Google Scholar]
  • 30.Kochhar R, Sethy PK, Sood A, Nagi B, Singh K. Concurrent pancreatic ductal changes in alcoholic liver disease. Journal of gastroenterology and hepatology. 2003;18(9):1067–70. [DOI] [PubMed] [Google Scholar]
  • 31.Adams HW, Webster PD 3rd, Mainz DL Association of chronic pancreatitis and alcoholic cirrhosis. Journal of the Medical Association of Georgia. 1980;69(9):759–63. [PubMed] [Google Scholar]
  • 32.Aparisi L, Sabater L, Del-Olmo J, Sastre J, Serra MA, Campello R, et al. Does an association exist between chronic pancreatitis and liver cirrhosis in alcoholic subjects? World journal of gastroenterology. 2008;14(40):6171–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Spicak J, Pulkertova A, Kralova-Lesna I, Suchanek P, Vitaskova M, Adamkova V. Alcoholic chronic pancreatitis and liver cirrhosis: coincidence and differences in lifestyle. Pancreatology : official journal of the International Association of Pancreatology (IAP) [et al. ]. 2012;12(4):311–6. [DOI] [PubMed] [Google Scholar]
  • 34.Darstein F, Konig C, Hoppe-Lotichius M, Grimm D, Knapstein J, Mittler J, et al. Impact of pancreatic comorbidities in patients with end-stage liver disease on outcome after liver transplantation. European journal of internal medicine. 2014;25(3):281–5. [DOI] [PubMed] [Google Scholar]
  • 35.Hayakawa T, Kondo T, Shibata T, Kitagawa M, Sakai Y, Sobajima H, et al. Exocrine pancreatic function in chronic liver diseases. The American journal of gastroenterology. 1991;86(2):201–4. [PubMed] [Google Scholar]
  • 36.Martin E, Bedossa P. Diffuse fibrosis of the pancreas: a peculiar pattern of pancreatitis in alcoholic cirrhosis. Gastroenterologie clinique et biologique. 1989;13(6–7):579–84. [PubMed] [Google Scholar]
  • 37.Wehmeyer MH, Dammermann W, Seiz O, Zinser ME, Galante A, Lohse AW, et al. Chronic pancreatitis in patients with liver cirrhosis negatively affects graft survival after liver transplantation. Pancreatology : official journal of the International Association of Pancreatology (IAP) [et al]. 2017;17(6):898–904. [DOI] [PubMed] [Google Scholar]
  • 38.Pace A, de Weerth A, Berna M, Hillbricht K, Tsokos M, Blaker M, et al. Pancreas and liver injury are associated in individuals with increased alcohol consumption. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2009;7(11):1241–6. [DOI] [PubMed] [Google Scholar]
  • 39.Dutta SK, Mobrahan S, Iber FL. Associated liver disease in alcoholic pancreatitis. The American journal of digestive diseases. 1978;23(7):618–22. [DOI] [PubMed] [Google Scholar]
  • 40.Jalleh RP, Gilbertson JA, Williamson RC, Foster CS. Morphological and immunohistochemical analysis of the human liver in chronic pancreatitis. Gut. 1991;32(11):1386–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Lesur G, Levy P, Flejou JF, Belghiti J, Fekete F, Bernades P. Factors predictive of liver histopathological appearance in chronic alcoholic pancreatitis with common bile duct stenosis and increased serum alkaline phosphatase. Hepatology (Baltimore, Md). 1993;18(5):1078–81. [PubMed] [Google Scholar]
  • 42.Agrawal P, Vaiphei K. Histomorphological features of pancreas and liver in chronic alcoholics--an analytical study in 390 autopsy cases. Indian journal of pathology & microbiology. 2014;57(1):2–8. [DOI] [PubMed] [Google Scholar]
  • 43.Schwarzer G.meta: An R Package for Meta-Analysis. R News. 2007;7(3):40–5. [Google Scholar]
  • 44.de la Iglesia-Garcia D, Vallejo-Senra N, Iglesias-Garcia J, Lopez-Lopez A, Nieto L, Dominguez-Munoz JE. Increased Risk of Mortality Associated With Pancreatic Exocrine Insufficiency in Patients With Chronic Pancreatitis. Journal of clinical gastroenterology. 2017. [DOI] [PubMed] [Google Scholar]
  • 45.Yang AL, Vadhavkar S, Singh G, Omary MB. Epidemiology of alcohol-related liver and pancreatic disease in the United States. Archives of internal medicine. 2008;168(6):649–56. [DOI] [PubMed] [Google Scholar]
  • 46.Angelini G, Merigo F, Degani G, Camplani N, Bovo P, Fratta Pasini A, et al. Association of chronic alcoholic liver and pancreatic disease: a prospective study. The American journal of gastroenterology. 1985;80(12):998–1003. [PubMed] [Google Scholar]
  • 47.Aoufi Rabih S, Garcia Agudo R, Legaz Huidobro ML, Ynfante Ferrus M, Gonzalez Carro P, Perez Roldan F, et al. Exocrine pancreatic insufficiency and chronic pancreatitis in chronic alcoholic liver disease: coincidence or shared toxicity? Pancreas. 2014;43(5):730–4. [DOI] [PubMed] [Google Scholar]
  • 48.Buchner AM, Sonnenberg A. Comorbid occurrence of liver and pancreas disease in United States military veterans. The American journal of gastroenterology. 2001;96(7):2231–7. [DOI] [PubMed] [Google Scholar]
  • 49.Chebli JM, Lobo E, Lanzoni VP, Das Neves MM. Asymptomatic hepatopathy is frequent in chronic alcoholic pancreatitis. The Mount Sinai journal of medicine, New York. 1997;64(2):125–9. [PubMed] [Google Scholar]
  • 50.Hastier P, Buckley MJ, Francois E, Peten EP, Dumas R, Caroli-Bosc FX, et al. A prospective study of pancreatic disease in patients with alcoholic cirrhosis: comparative diagnostic value of ERCP and EUS and long-term significance of isolated parenchymal abnormalities. Gastrointestinal endoscopy. 1999;49(6):705–9. [DOI] [PubMed] [Google Scholar]
  • 51.Renner IG, Savage WT 3rd, Stace NH, Pantoja JL, Schultheis WM, Peters RL Pancreatitis associated with alcoholic liver disease. A review of 1022 autopsy cases. Digestive diseases and sciences. 1984;29(7):593–9. [DOI] [PubMed] [Google Scholar]
  • 52.Soni A, Singh B, Nijhawan S, Mathur A, Gupta G. Chronic liver disease in alcohol-related chronic pancreatitis patients: Does lightning strike twice? Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology. 2015;34(4):345–6. [DOI] [PubMed] [Google Scholar]
  • 53.Chedid A, Mendenhall CL, Tosch T, Chen T, Rabin L, Garcia-Pont P, et al. Significance of megamitochondria in alcoholic liver disease. Gastroenterology. 1986;90(6):1858–64. [DOI] [PubMed] [Google Scholar]
  • 54.Frossard JL, Giostra E, Rubbia-Brandt L, Hadengue A, Spahr L. The role of transient elastography in the detection of liver disease in patients with chronic pancreatitis. Liver international : official journal of the International Association for the Study of the Liver. 2013;33(7):1121–7. [DOI] [PubMed] [Google Scholar]
  • 55.Gullo L, Casadei R, Campione O, Grigioni W, Marrano D. Alcoholic liver disease in alcoholic chronic pancreatitis: a prospective study. The Italian journal of gastroenterology. 1995;27(2):69–72. [PubMed] [Google Scholar]
  • 56.Hietanen D, Raty S, Sand J, Makela T, Laukkarinen J, Collin P. Liver stiffness measured by transient elastography in patients with acute pancreatitis. Pancreatology : official journal of the International Association of Pancreatology (IAP) [et al. ]. 2014;14(2):91–4. [DOI] [PubMed] [Google Scholar]
  • 57.Montalto G, Cambon P, Bernard JP, Durbec JP, Sarles H. Chronic pancreatitis in southern France. Evolution of dietary habits and natural history. Frequency of liver cirrhosis and other histological changes. European Journal of Gastroenterology and Hepatology. 1992;4(9):733–8. [Google Scholar]
  • 58.Nguyen TA, DeShazo JP, Thacker LR, Puri P, Sanyal AJ. The Worsening Profile of Alcoholic Hepatitis in the United States. Alcoholism, clinical and experimental research. 2016;40(6):1295–303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Otete HE, Orton E, Fleming KM, West J. Alcohol-attributable healthcare attendances up to 10 years prior to diagnosis of alcoholic cirrhosis: a population based case-control study. Liver international : official journal of the International Association for the Study of the Liver. 2016;36(4):538–46. [DOI] [PubMed] [Google Scholar]
  • 60.Tapper EB, Lok AS. Use of Liver Imaging and Biopsy in Clinical Practice. The New England journal of medicine. 2017;377(8):756–68. [DOI] [PubMed] [Google Scholar]
  • 61.Parakh A, Tirkes T. Advanced imaging techniques for chronic pancreatitis. Abdom Radiol (NY). 2020;45(5):1420–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Catalano MF, Sahai A, Levy M, Romagnuolo J, Wiersema M, Brugge W, et al. EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification. Gastrointestinal endoscopy. 2009;69(7):1251–61. [DOI] [PubMed] [Google Scholar]
  • 63.Clemens DL, Mahan KJ. Alcoholic pancreatitis: lessons from the liver. World journal of gastroenterology. 2010;16(11):1314–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Rusyn I, Bataller R. Alcohol and toxicity. Journal of hepatology. 2013;59(2):387–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Testino G, Leone S, Fagoonee S. Alcoholic liver disease and vitamin D deficiency. Minerva Med. 2018;109(5):341–3. [DOI] [PubMed] [Google Scholar]
  • 66.Takase M, Suda K, Suzuki F, Nakamura T, Futagawa S. A histopathologic study of localized portal hypertension as a consequence of chronic pancreatitis. Archives of pathology & laboratory medicine. 1997;121(6):612–4. [PubMed] [Google Scholar]
  • 67.Li H, Yang Z, Tian F. Clinical Characteristics and Risk Factors for Sinistral Portal Hypertension Associated with Moderate and Severe Acute Pancreatitis: A Seven-Year Single-Center Retrospective Study. Med Sci Monit. 2019;25:5969–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Rasineni K, Srinivasan MP, Balamurugan AN, Kaphalia BS, Wang S, Ding WX, et al. Recent Advances in Understanding the Complexity of Alcohol-Induced Pancreatic Dysfunction and Pancreatitis Development. Biomolecules. 2020;10(5). [DOI] [PMC free article] [PubMed] [Google Scholar]

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