Gastroenterology Today Winter 2023

Gastroenterology Today Winter 2023

Gastroenterology Today Winter 2023


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Volume 34 No. 4 <strong>Winter</strong> <strong>2023</strong>



<strong>Gastroenterology</strong> <strong>Today</strong><br />


7 FEATURE Timing of endoscopy in patients with cirrhosis<br />

and acute variceal bleeding: a single-center<br />

retrospective study<br />

19 FEATURE Non-alcoholic fatty liver disease in<br />

hemochromatosis probands with iron<br />

overload and HFE p.C282Y/p.C282Y<br />


This issue edited by:<br />

Aaron Bhakta<br />

c/o Media Publishing Company<br />

Greenoaks, Lockhill<br />

Upper Sapey, Worcester, WR6 6XR<br />


Media Publishing Company<br />

Greenoaks, Lockhill<br />

Upper Sapey, Worcester, WR6 6XR<br />

Tel: 01886 853715<br />

E: info@mediapublishingcompany.com<br />

www.ambulanceukonline.com<br />


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References:<br />

1. NHS Inform. Constipation. Nov <strong>2023</strong>. Available online at:<br />

https://www.nhsinform.scot/illnesses-and-conditions/stomach-liver-andgastrointestinal-tract/constipation#:~:text=It’s%20estimated%20that%20around%20<br />

1,older%20adults%20and%20during%20pregnancy. Accessed Nov <strong>2023</strong>.<br />

2. NICE. Scenario: Constipation in adults. <strong>2023</strong>. Available at:<br />

https://cks.nice.org.uk/topics/constipation/management/adults/ Accessed Nov <strong>2023</strong><br />

3. Jalanka et al. Int. J. Mol. Sci 2019, 20(2) 433 https://doi.org/10.3390/ijms20020433<br />

4. Riaz G and Chopra R. Biomedicine & Pharmacotherapy 2018; 102: 575-586.<br />

https://doi.org/10.1016/j.biopha.2018.03.023<br />

GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />





“Data from the<br />

British Liver<br />

Trust shows<br />

that liver<br />

disease is the<br />

only major noncommunicable<br />

disease in<br />

the UK where<br />

death rates<br />

are rising.”<br />

Christmas <strong>2023</strong>.<br />

Chronic liver disease is a significant cause of morbidity and mortality worldwide. Cases of non-alcoholic<br />

related fatty liver disease (NAFLD) and alcohol related cirrhosis are rising in many parts of the world.<br />

As a result, we are seeing more patients presenting to hospital with decompensated cirrhosis and the<br />

associated complications.<br />

One such presentation of decompensated cirrhosis is acute variceal bleeding, for which the initial<br />

management is resuscitation and pharmacological treatment followed by upper endoscopy. A number<br />

of organisations and societies around the world suggest endoscopy within 12 hours of presentation, but<br />

the optimal timing remains a contentious matter as previous studies on the topic failed to reach similar<br />

conclusions. In this edition of <strong>Gastroenterology</strong> <strong>Today</strong> we feature a single-centre retrospective study looking<br />

at this issue.<br />

Aaron Bhakta<br />

Stronger Together<br />

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The unique strength of of our our collective organisation will will continue<br />

to to uphold our our mission of of HELPING OUR CUSTOMERS CREATE<br />


GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />

Publishers Comment<br />

On behalf of everyone involved with the publishing of <strong>Gastroenterology</strong> <strong>Today</strong> I would like to say a big<br />

thank you to our contributors for their input and a special thank you to our advertisers as without their<br />

ongoing support we would not be able to print and despatch copies of this very unique publication to<br />

all <strong>Gastroenterology</strong> Departments and Endoscopy Units. Wishing you all a very happy Christmas and<br />

prosperous 2024.<br />

Terry Gardner<br />

Publisher<br />

GASTROENTEROLOGY TODAY - SUMMER <strong>2023</strong><br />

GASTROENTEROLOGY TODAY - SUMMER <strong>2023</strong><br />

Come join join us us<br />

at at BSG!<br />

Stand A26<br />

The Arena<br />

4<br />

12 12<br />







Mengyuan Peng 1,2† , Zhaohui Bai 1,3† , Deli Zou 1† , Shixue Xu 1 , Chunmei Wang 1 , Metin Başaranoğlu 4 ,<br />

Cyriac Abby Philips 5 , Xiaozhong Guo 1 , Xiaodong Shao 1* and Xingshun Qi 1,2,3*<br />

Peng et al. BMC <strong>Gastroenterology</strong> (<strong>2023</strong>) 23:219 https://doi.org/10.1186/s12876-023-02766-8<br />


Abstract<br />

Background The optimal timing of endoscopy in liver cirrhosis<br />

with acute variceal bleeding (AVB) remains controversial in current<br />

guidelines and studies.<br />

Methods Consecutive patients with liver cirrhosis and AVB were<br />

screened. The timing of endoscopy was calculated from the last<br />

presentation of AVB or the admission to endoscopy. Early endoscopy<br />

was defined as the interval < 12 h, < 24 h, or < 48 h. A 1:1 propensity<br />

score matching (PSM) analysis was performed. Five-day failure to<br />

control bleeding and in-hospital mortality were evaluated.<br />

Results Overall, 534 patients were included. When the timing of<br />

endoscopy was calculated from the last presentation of AVB, PSM<br />

analysis demonstrated that the rate of 5-day failure to control bleeding<br />

was significantly higher in early endoscopy group defined as < 48<br />

h (9.7% versus 2.4%, P = 0.009), but not < 12 h (8.7% versus 6.5%,<br />

P = 1.000) or < 24 h (13.4% versus 6.2%, P = 0.091), and that the<br />

in-hospital mortality was not significantly different between early and<br />

delayed endoscopy groups (< 12 h: 6.5% versus 4.3%, P = 1.000;


Peng et al. BMC <strong>Gastroenterology</strong> (<strong>2023</strong>) 23:219<br />

Page 4 of 9<br />


AVB, but not significantly associated with control of bleeding [11].<br />

However, multiple factors, including the definition regarding timing of<br />

endoscopy, presentation of AVB, hemodynamic status, and severity<br />

of liver disease, could not be sufficiently addressed or adjusted in our<br />

meta-analysis.<br />

More recently, a large randomized controlled trial (RCT) did not<br />

demonstrate any significant difference in 30-day mortality between<br />

patients with upper gastrointestinal bleeding treated with urgent<br />

endoscopy (< 6 h) and early endoscopy (6-24 h) [12]. However, these<br />

findings may not be appropriate for the management of AVB, because<br />

most patients included in this RCT were noncirrhotic (91.8%), and the<br />

source of bleeding was mostly non-variceal (82.9%) [12].<br />

Herein, we conducted a retrospective study to further shed light on<br />

whether early endoscopy was beneficial for patients with cirrhosis<br />

and AVB, especially by adjusting for the definitions regarding timing of<br />

endoscopy and early endoscopy, manifestation of AVB, and severity of<br />

liver disease.<br />

Methods<br />

Outcomes<br />

Outcomes of interest included 5-day failure to control bleeding and<br />

in-hospital death.<br />

Definitions<br />

Timing of endoscopy was calculated according to the interval from<br />

the last presentation of AUGIB or the admission to endoscopy.<br />

Accordingly, eligible patients were divided into early and delayed<br />

endoscopy groups according to three different intervals, including<br />

< 12 h versus ≥ 12 h, < 24 h versus ≥ 24 h, and < 48 h versus ≥ 48 h.<br />

AUGIB was defined as hematemesis or melena within 120 h before<br />

admission [2]. Variceal bleeding was defined as: (1) the presence<br />

of active bleeding from varices on endoscopy; (2) signs of recent<br />

bleeding, such as white nipple; or (3) variceal bleeding would also be<br />

considered, if varices were the only lesion in the stomach, and blood<br />

was found in the stomach or endoscopy was performed 24 h after<br />

bleeding [3]. Five-day failure to control bleeding was defined as the<br />

presence of any of the following within 5 days after endoscopy: (1)<br />

vomiting fresh blood or aspirating more than 100 ml fresh blood for<br />

patients with naso-gastric tube placement after 2 h of endoscopy; (2)<br />

reduction of 3 g/L hemoglobin without transfusion; or (3) death [2].<br />

GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />

Study design<br />

Patients with liver cirrhosis and AVB were screened from our<br />

retrospective database of 982 patients with liver cirrhosis and acute<br />

upper gastrointestinal bleeding (AUGIB) who were consecutively<br />

admitted to our hospital between January 2010 and June 2014 [13, 14]<br />

and our prospective database of 346 patients with liver cirrhosis and<br />

AUGIB who were consecutively admitted to our department between<br />

December 2014 and January 2022 [15, 16]. Age and comorbidities<br />

were not limited.<br />

Exclusion criteria were as follows: (1) patients did not undergo<br />

endoscopy or those with contraindications for endoscopy; (2) patients<br />

underwent endoscopy at other hospitals or emergency department or<br />

outpatient clinics of our hospital; (3) endoscopy was performed beyond<br />

5 days after the last episode of AUGIB; (4) the timing of endoscopy<br />

was ambiguous according to the medical records; and (5) the source<br />

of AUGIB was non-variceal or could not be accurately identified<br />

according to the medical records or endoscopic reports.<br />

The study protocol has been approved by the Medical Ethical<br />

Committee of the General Hospital of Northern Theater Command with<br />

an approval number (Y [2022] 019) and performed according to the<br />

Declaration of Helsinki. Written informed consents were waived due to<br />

the retrospective nature of this study.<br />

Data collection<br />

Primary data extracted included age, gender, clinical manifestations,<br />

etiology of liver disease, presence of hepatocellular carcinoma,<br />

systolic blood pressure, heart rate, hemoglobin, white blood cell,<br />

platelet count, albumin, alanine aminotransferase, blood urea nitrogen,<br />

serum creatinine, sodium, and prothrombin time (PT) at admission.<br />

Active variceal bleeding on endoscopy, source of variceal bleeding,<br />

endoscopic variceal therapy, surgery or interventional treatment, Child-<br />

Pugh score and class, and model for end-stage liver disease (MELD)<br />

score were also recorded.<br />

Management of AUGIB<br />

Generally, the management of AUGIB is in accordance with the current<br />

practice guideline, which primarily includes fluid resuscitation, blood<br />

transfusion, pharmacological treatment, and endoscopic treatment<br />

[1, 8]. Red blood cell transfusion would be given, if patients had a<br />

hemoglobin level of < 60-80 g/L, or they had active bleeding and<br />

were hemodynamically unstable. Pharmacological treatment included<br />

intravenous vasoactive drugs (terlipressin, somatostatin, or octreotide)<br />

and highdose proton pump inhibitors. Timing of endoscopy was<br />

decided at the discretion of attending physicians according to the<br />

patients’ age, consciousness, comorbidities, and hemodynamics.<br />

Endoscopic treatment was performed by experienced endoscopists.<br />

Endoscopic variceal therapy includes endoscopic variceal ligation,<br />

sclerotherapy, and injection of tissue adhesive. Endoscopic variceal<br />

ligation was primarily employed for the treatment of acute esophageal<br />

variceal bleeding, sclerotherapy was considered when ligation was<br />

technically difficult or active variceal bleeding was observed on<br />

endoscopy, and injection of tissue adhesive was primarily used for the<br />

treatment of acute gastric variceal bleeding. Repeat endoscopy was<br />

often recommended 2–4 weeks after the first endoscopic variceal<br />

therapy, with additional endoscopic variceal treatment(s), if necessary.<br />

If endoscopy failed to control bleeding, patients would undergo surgery<br />

or interventional treatment.<br />

Statistical analyses<br />

Continuous variables were presented as mean ± standard deviation<br />

and median (range), and categorical variables were presented as<br />

frequency (percentage). The nonparametric Mann-Whitney U test was<br />

used for continuous variables, and the chi-square test and Fisher’s<br />

exact test were used for categorical variables to explore the difference<br />

between early and delayed endoscopy groups.<br />

Logistic and Cox regression analyses were performed to identify<br />

whether early endoscopy was an independent predictor of 5-day<br />

failure to control bleeding or in-hospital death. Odds ratios (ORs)<br />

Fig. 1 Flowchart of patient selection<br />

in-hospital death (HR = 2.828, 95% CI: 0.706–11.320,<br />

P = 0.142).<br />

In the PSM analysis, 46 patients were matched to each<br />

group (Supplementary Table 2). There was no significant<br />

difference in rate of 5-day failure to control bleeding or<br />

in-hospital mortality between the two groups (Table 2).<br />

< 24 h versus ≥ 24 h. In the overall-analysis, early<br />

endoscopy group was significantly older and had higher<br />

proportions of HCV infection, hematemesis, systolic<br />

blood pressure < 90 mmHg, Child-Pugh class B/C, and<br />

active variceal bleeding on endoscopy and white blood<br />

cell than delayed endoscopy group (Supplementary<br />

Table 3). Early endoscopy group had significantly higher<br />

rate of 5-day failure to control bleeding and in-hospital<br />

mortality than delayed endoscopy group (Table 2).<br />

and hazard ratios (HRs) with 95% confidence intervals (CIs) were<br />

calculated. A 1:1 propensity score matching (PSM) analysis was<br />

performed by using a matching tolerance of 0.02 and greedymatching<br />

algorithm without replacement to compare the rate of 5-day failure<br />

to control bleeding and in-hospital mortality between early and<br />

delayed endoscopy groups. After PSM, the comparability of baseline<br />

characteristics between the groups was re-evaluated. Matching<br />

factors included age, gender, systolic blood pressure < 90mmHg,<br />

heart rate > 100 beats per minute, PT, Child-Pugh score, MELD score,<br />

hematemesis at admission, active variceal bleeding on endoscopy, and<br />

endoscopic variceal therapy. A two-tailed P < 0.05 was considered<br />

statistically significant. All statistical analyses were performed with IBM<br />

SPSS 26.0 (IBM Corp, Armonk, NY, USA).<br />

Results<br />

Patients<br />

Overall, 534 patients with cirrhosis and AVB were included (Fig. 1).<br />

Patient characteristics were shown in Table 1. The median age was<br />

Multivariate logistic regression analysis demonstrated<br />

that the interval from last presentation of AVB to endoscopy<br />

< 24 h was significantly associated with a higher rate<br />

of 5-day failure to control bleeding (OR = 6.065, 95% CI:<br />

2.336–15.749; P < 0.001). Multivariate Cox regression<br />

analysis showed that the interval from last presentation<br />

of AVB to endoscopy < 24 h was not significantly associated<br />

with in-hospital death (HR = 1.400, 95% CI: 0.403–<br />

4.860, P = 0.597).<br />

In the PSM analysis, 97 patients were matched to each<br />

group (Supplementary Table 4). There was no significant<br />

difference in rate of 5-day failure to control bleeding or<br />

in-hospital mortality between the two groups (Table 2).<br />

< 48 h versus ≥ 48 h. In the overall-analysis, early<br />

endoscopy group was significantly older and had significantly<br />

higher proportions of HCV infection,<br />

55.66 years (range: 6.28–92.31 years), and 376 (70.4%) patients<br />

were male. Hematemesis at admission in 332 (62.2%) patients. Most<br />

patients had Child-Pugh class B/C (333/498, 66.9%). Median MELD<br />

score was 10.51 (range: 6.43–38.01). Active bleeding was observed<br />

under endoscopy in 39 (7.4%) patients. The rate of 5-day failure to<br />

control bleeding was 5.1% (n = 27). The in-hospital mortality was<br />

2.4% (n = 13). The causes of death included massive gastrointestinal<br />

bleeding (n = 8), end-stage liver disease with multiple organ failure<br />

(n = 4), and cardiogenic shock (n = 1).<br />

Time to endoscopy according to the interval from the last<br />

presentation of AVB to endoscopy<br />

< 12 h versus ≥ 12 h. In the overall-analysis, early endoscopy group<br />

had significantly higher proportions of hepatitis C virus (HCV) infection<br />

and systolic blood pressure < 90 mmHg and white blood cell than<br />

delayed endoscopy group (Supplementary Table 1). Early endoscopy<br />

group had significantly higher rate of 5-day failure to control bleeding<br />

and in-hospital mortality than delayed endoscopy group (Table 2).<br />

GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />

8 9

Peng et al. BMC <strong>Gastroenterology</strong> (<strong>2023</strong>) 23:219<br />


Page 5 of 9<br />

Peng et al. BMC <strong>Gastroenterology</strong> (<strong>2023</strong>) 23:219<br />

Page 6 of 9<br />


GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />

Table 1 Characteristics of included patients<br />

Variables No. Pts Mean ± SD or<br />

Median (Range) or<br />

Frequency (Percentage)<br />

Age (years) 534 55.66 (6.28–92.31)<br />

55.78 ± 11.61<br />

Male 534 376 (70.4%)<br />

Etiology of underlying liver diseases 534<br />

Hepatitis B virus 222 (41.6%)<br />

Hepatitis C virus 47 (8.8%)<br />

Alcohol abuse 150 (28.1%)<br />

Hepatocellular carcinoma 534 48 (9.0%)<br />

Hematemesis 534 332 (62.2%)<br />

Hemodynamics<br />

Heart rate (beats per minute) 534 80.00 (44.00-148.00)<br />

83.36 ± 13.24<br />

Heart rate > 100 beats per minute 534 54 (10.1%)<br />

Systolic blood pressure (mmHg) 533 115.00 (75.00-176.00)<br />

116.07 ± 17.59<br />

Systolic blood pressure < 90mmHg 533 18 (3.4%)<br />

Laboratory tests<br />

Hemoglobin (g/L) 533 73.00 (23.00-158.00)<br />

77.53 ± 22.51<br />

White blood cell (10 12 /L) 533 4.40 (1.00-46.10)<br />

5.45 ± 3.98<br />

Platelet count (10 9 /L) 533 72.00 (15.00-457.00)<br />

87.44 ± 58.82<br />

Total bilirubin (µmol/L) 529 19.90 (3.30-187.40)<br />

25.01 ± 18.35<br />

Albumin (g/L) 524 30.50 (10.00-50.70)<br />

30.57 ± 6.53<br />

Alanine aminotransferase (U/L) 527 22.73 (5.00-1064.00)<br />

32.70 ± 58.03<br />

Blood urea nitrogen (mmol/L) 512 8.03 (1.54–42.83)<br />

8.95 ± 4.79<br />

Serum creatinine (µmol/L) 510 62.00 (25.00-715.00)<br />

69.30 ± 45.29<br />

Sodium (mmol/L) 524 138.5 (109.2-160.10)<br />

138.44 ± 4.22<br />

Prothrombin time (seconds) 510 16.00 (10.50–55.00)<br />

16.85 ± 4.00<br />

Child-Pugh score 498 7.00 (5.00–13.00)<br />

7.47 ± 1.82<br />

Child-Pugh class A/B + C 498 165 (33.1%)/333 (66.9%)<br />

MELD score 502 10.51 (6.43–38.01)<br />

11.92 ± 4.61<br />

Source of variceal bleeding 519 *<br />

Esophageal varices (%) 313 (60.3%)<br />

Gastric varices (%) 77 (14.8%)<br />

Esophageal and gastric varices (%) 129 (24.9%)<br />

Active variceal bleeding on endoscopy 528 # 39 (7.4%)<br />

Endoscopic variceal therapy 534 496 (92.9%)<br />

Surgery or interventional treatment 534 3 (0.6%)<br />

Rate of 5-day failure to control bleeding 534 27 (5.1%)<br />

In-hospital mortality 534 13 (2.4%)<br />

Abbreviations: MELD, model for end-stage liver disease. Notes: * Source of variceal bleeding was unclear in 15 patients because of missing medical records or poor<br />

visual fields under endoscopy; # Active variceal bleeding on endoscopy cannot be identified in 6 patients because of missing endoscopic reports.<br />

Table 2 Outcomes according to the timing of endoscopy defined as the interval from the last presentation of AVB to endoscopy<br />

Overall analysis<br />

< 12h ≥ 12h P value < 24h ≥ 24h P value < 48h ≥ 48h P value<br />

(N = 55) (N = 434)<br />

(N = 114) (N = 357)<br />

(N = 226) (N = 242)<br />

Rate of 5-day failure to control bleeding 6 (10.9%) 14 (3.2%) 0.007 15 (13.2%) 8 (2.2%) < 0.001 20 (8.8%) 5 (2.1%) 0.001<br />

In-hospital mortality 5 (9.1%) 6 (1.4%) < 0.001 6 (5.3%) 6 (1.7%) 0.035 8 (3.5%) 5 (2.1%) 0.332<br />

PSM analysis<br />

hematemesis, systolic blood pressure < 90 mmHg, Child-<br />

Multivariate logistic regression analysis demonstrated that the interval<br />

Pugh class B/C, and active variceal bleeding on endoscopy,<br />

white blood cell, and blood urea nitrogen than<br />

from last presentation of AVB to endoscopy < 12 h was not significantly<br />

associated with 5-day failure to control bleeding (OR = 2.889, 95% CI:<br />

delayed endoscopy group (Supplementary Table 5). Early<br />

0.912–9.151; P = 0.071). Multivariate Cox regression analysis showed<br />

endoscopy group had a significantly higher rate of 5-day<br />

that the interval from last presentation of AVB to endoscopy < 12 h was<br />

failure to control bleeding than delayed endoscopy group,<br />

not significantly associated with in-hospital death (HR = 2.828, 95% CI:<br />

but a statistically similar in-hospital mortality (Table 2).<br />

0.706–11.320, P = 0.142).<br />

Multivariate logistic regression analysis demonstrated<br />

that the interval from last presentation of AVB to endoscopy<br />

< 48 h was significantly associated with a higher rate<br />

In the PSM analysis, 46 patients were matched to each group<br />

(Supplementary Table 2). There was no significant difference in rate of<br />

of 5-day failure to control bleeding (OR = 4.171, 95% CI:<br />

5-day failure to control bleeding or in-hospital mortality between the<br />

1.486–11.708; P = 0.007). Cox regression analysis showed<br />

two groups (Table 2).<br />

that the interval from last presentation of AVB to endoscopy<br />

< 48 h was not significantly associated with in-hospital<br />

death (HR = 0.808, 95% CI: 0.237–2.750, P = 0.733).<br />

< 24 h versus ≥ 24 h. In the overall-analysis, early endoscopy group<br />

was significantly older and had higher proportions of HCV infection,<br />

In the PSM analysis, 165 patients were matched to each<br />

hematemesis, systolic blood pressure < 90 mmHg, Child-Pugh class<br />

group (Supplementary Table 6). Early endoscopy group<br />

B/C, and active variceal bleeding on endoscopy and white blood<br />

had a significantly higher rate of 5-day failure to control<br />

cell than delayed endoscopy group (Supplementary Table 3). Early<br />

bleeding than delayed endoscopy group, but a statistically<br />

endoscopy group had significantly higher rate of 5-day failure to control<br />

similar in-hospital mortality (Table 2).<br />

bleeding and in-hospital mortality than delayed endoscopy group<br />

(Table 2).<br />

Time to endoscopy according to the interval from the<br />

admission to endoscopy<br />

Multivariate logistic regression analysis demonstrated that the interval<br />

< 12 h versus ≥ 12 h. In the overall-analysis, early endoscopy<br />

group was significantly older and had significantly<br />

from last presentation of AVB to endoscopy < 24 h was associated with a higher rate of 5-day failure to control bleeding (OR =<br />

higher proportions of HCV infection, Child-Pugh class<br />

6.065, 95% CI: 2.336–15.749; P < 0.001). Multivariate Cox regression<br />

B/C, and active variceal bleeding on endoscopy, white<br />

analysis showed that the interval from last presentation of AVB to<br />

blood cell, total bilirubin, blood urea nitrogen, Childendoscopy<br />

< 24 h was not significantly associated with in-hospital<br />

Pugh score, and MELD score than delayed endoscopy<br />

death (HR = 1.400, 95% CI: 0.403–4.860, P = 0.597).<br />

group (Supplementary Table 7). There was no significant<br />

difference in rate of 5-day failure to control bleeding or<br />

In the PSM analysis, 97 patients were matched to each group<br />

in-hospital mortality between the two groups (Table 3).<br />

(Supplementary Table 4). There was no significant difference in rate of<br />

5-day failure to control bleeding or in-hospital mortality between the<br />

two groups (Table 2).<br />

< 12h<br />

(N = 46)<br />

≥ 12h<br />

(N = 46)<br />

P value<br />

< 24h<br />

(N = 97)<br />

≥ 24h<br />

(N = 97)<br />

P value<br />

< 48h<br />

(N = 165)<br />

≥ 48h<br />

(N = 165)<br />

Rate of 5-day failure to control bleeding 4 (8.7%) 3 (6.5%) 1.000 13 (13.4%) 6 (6.2%) 0.091 16 (9.7%) 4 (2.4%) 0.009<br />

In-hospital mortality 3 (6.5%) 2 (4.3%) 1.000 4 (4.1%) 3 (3.1%) 1.000 5 (3.0%) 4 (2.4%) 1.000<br />

Abbreviations: AVB, acute variceal bleeding; PSM, propensity score matching<br />

P value<br />

Table 3 Outcomes according to the timing of endoscopy defined as the interval from the admission to endoscopy<br />

Overall analysis<br />

< 12h ≥ 12h P value < 24h ≥ 24h P value < 48h ≥ 48h P value<br />

(N = 75) (N = 453)<br />

(N = 175) (N = 349)<br />

(N = 289) (N = 236)<br />

Rate of 5-day failure to control bleeding 5 (6.7%) 21 (4.6%) 0.451 10 (5.7%) 17 (4.9%) 0.680 13 (4.5%) 13 (5.5%) 0.596<br />

In-hospital mortality 4 (5.3%) 8 (1.8%) 0.055 7 (4.0%) 6 (1.7%) 0.113 8 (2.8%) 5 (2.1%) 0.634<br />

PSM analysis<br />

< 12h<br />

(N = 63)<br />

≥ 12h<br />

(N = 63)<br />

P value<br />

< 24h<br />

(N = 155)<br />

≥ 24h<br />

(N = 155)<br />

P value<br />

< 48h<br />

(N = 199)<br />

≥ 48h<br />

(N = 199)<br />

Rate of 5-day failure to control bleeding 3 (4.8%) 8 (12.7%) 0.205 8 (5.2%) 12 (7.7%) 0.355 9 (4.5%) 12 (6.0%) 0.501<br />

In-hospital mortality 3 (4.8%) 3 (4.8%) 1.000 6 (3.9%) 4 (2.6%) 0.750 4 (2.0%) 5 (2.5%) 1.000<br />

Abbreviations: PSM, propensity score matching<br />

P value<br />

Multivariate logistic regression analysis demonstrated<br />

< 48 h versus ≥ 48 h. In the overall-analysis, early endoscopy group<br />

that the interval from admission to endoscopy < 12 h was<br />

was significantly older and had significantly higher proportions of HCV<br />

not significantly associated with 5-day failure to control<br />

infection, hematemesis, systolic blood pressure < 90 mmHg, Childbleeding<br />

(OR = 0.873, 95% CI: 0.243–3.144; P = 0.836).<br />

Pugh class B/C, and active variceal bleeding on endoscopy, white<br />

blood<br />

Multivariate<br />

cell, and blood<br />

Cox<br />

urea<br />

regression<br />

nitrogen than<br />

analysis<br />

delayed endoscopy<br />

showed that<br />

group<br />

the<br />

(Supplementary<br />

interval from<br />

Table<br />

admission<br />

5). Early<br />

to<br />

endoscopy<br />

endoscopy<br />

group<br />

<<br />

had<br />

12 h<br />

a significantly<br />

was not significantly<br />

higher rate of<br />

associated<br />

5-day failure to<br />

with<br />

control<br />

in-hospital<br />

bleeding than<br />

death<br />

delayed<br />

(HR<br />

endoscopy<br />

= 1.981,<br />

group, 95% CI: but 0.467–8.406, a statistically similar P = 0.354). in-hospital mortality (Table 2).<br />

In the PSM analysis, 63 patients were matched to each<br />

Multivariate group (Supplementary logistic regression Table analysis 8). demonstrated There was that no significant<br />

the interval<br />

from difference last presentation in rate of of AVB 5-day to endoscopy failure to < 48 control h was significantly bleeding or<br />

associated in-hospital with mortality a higher rate between of 5-day the failure two to control groups bleeding (Table(OR<br />

3).<br />

= 4.171, < 2495% h versus CI: 1.486–11.708; ≥ 24 h. P = In 0.007). the Cox overall-analysis, regression analysis early<br />

showed endoscopy that the group interval was from significantly last presentation older of AVB and to endoscopy had significantly<br />

48 h was higher not significantly proportion associated of Child-Pugh with in-hospital class death B/C (HR = and<br />

<<br />

0.808, Child-Pugh 95% CI: 0.237–2.750, score than P delayed = 0.733). endoscopy group (Supplementary<br />

Table 9). There was no significant difference<br />

In in the rate PSM of analysis, 5-day failure 165 patients to control were matched bleeding to each or group in-hospital<br />

(Supplementary mortality between Table 6). the Early two endoscopy groups group (Table had 3). a significantly<br />

higher Multivariate rate of 5-day logistic failure to regression control bleeding analysis than delayed demonstrated<br />

endoscopy<br />

group, that the but interval a statistically from similar admission in-hospital to mortality endoscopy (Table < 2). 24 h was<br />

not significantly associated with 5-day failure to control<br />

Time bleeding to endoscopy (OR = 0.867, according 95% to the CI: interval 0.353–2.132; from the admission P = 0.756).<br />

to Multivariate endoscopy Cox regression analysis showed that the<br />

< interval 12 h versus from ≥ 12 admission h. In the overall-analysis, to endoscopy early < 24 endoscopy h was not group sig-<br />

was significantly associated older and with had significantly in-hospital higher death proportions (HR = of 2.554,<br />

HCV 95% infection, CI: 0.747–8.732, Child-Pugh class P = 0.135). B/C, and active variceal bleeding<br />

on In endoscopy, the PSM white analysis, blood cell, 155 total patients bilirubin, were blood matched urea nitrogen, to each<br />

Child-Pugh group (Supplementary score, and MELD Table score than 10). delayed There was endoscopy no significant group<br />

(Supplementary difference in Table rate 7). of There 5-day was failure no significant to control difference bleeding rate of or<br />

5-day in-hospital failure to mortality control bleeding between or in-hospital the two mortality groups between (Table the 3).<br />

two<br />

<<br />

groups<br />

48 h<br />

(Table<br />

versus<br />

3).<br />

≥ 48 h. In the overall-analysis, early<br />

endoscopy group was significantly older than delayed<br />

Multivariate logistic regression analysis demonstrated that the interval<br />

from admission to endoscopy < 12 h was not significantly associated<br />

GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />

10 11



GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />

with 5-day failure to control bleeding (OR = 0.873, 95% CI: 0.243–<br />

3.144; P = 0.836). Multivariate Cox regression analysis showed that<br />

the interval from admission to endoscopy < 12 h was not significantly<br />

associated with in-hospital death (HR = 1.981, 95% CI: 0.467–8.406,<br />

P = 0.354).<br />

In the PSM analysis, 63 patients were matched to each group<br />

(Supplementary Table 8). There was no significant difference in rate of<br />

5-day failure to control bleeding or in-hospital mortality between the<br />

two groups (Table 3).<br />

< 24 h versus ≥ 24 h. In the overall-analysis, early endoscopy group<br />

was significantly older and had significantly higher proportion of Child-<br />

Pugh class B/C and Child-Pugh score than delayed endoscopy group<br />

(Supplementary Table 9). There was no significant difference in rate of<br />

5-day failure to control bleeding or in-hospital mortality between the<br />

two groups (Table 3).<br />

Multivariate logistic regression analysis demonstrated that the interval<br />

from admission to endoscopy < 24 h was not significantly associated<br />

with 5-day failure to control bleeding (OR = 0.867, 95% CI: 0.353–<br />

2.132; P = 0.756). Multivariate Cox regression analysis showed that<br />

the interval from admission to endoscopy < 24 h was not significantly<br />

associated with in-hospital death (HR = 2.554, 95% CI: 0.747–8.732,<br />

P = 0.135).<br />

In the PSM analysis, 155 patients were matched to each group<br />

(Supplementary Table 10). There was no significant difference in rate<br />

of 5-day failure to control bleeding or in-hospital mortality between the<br />

two groups (Table 3).<br />

< 48 h versus ≥ 48 h. In the overall-analysis, early endoscopy group<br />

was significantly older than delayed endoscopy group (Supplementary<br />

Table 11). There was no significant difference in rate of 5-day failure<br />

to control bleeding or in-hospital mortality between the two groups<br />

(Table 3).<br />

Multivariate logistic regression analysis demonstrated that the interval<br />

from admission to endoscopy < 48 h was not significantly associated<br />

with 5-day failure to control bleeding (OR = 0.643, 95% CI: 0.275–<br />

1.506; P = 0.309). Multivariate Cox regression analysis showed that<br />

the interval from admission to endoscopy < 48 h was not significantly<br />

associated with in-hospital death (HR = 1.513, 95% CI: 0.416–5.499,<br />

P = 0.529).<br />

In the PSM analysis, 199 patients were matched to each group<br />

(Supplementary Table 12). There was no significant difference in rate<br />

of 5-day failure to control bleeding or in-hospital mortality between the<br />

two groups (Table 3).<br />

Subgroup analyses<br />

Subgroup analyses were performed according to the manifestations<br />

of AUGIB (hematemesis versus nonhematemesis) and severity of liver<br />

diseases (Child-Pugh class A versus Child-Pugh class B/C). The results<br />

were shown in Supplementary Table 13 and Supplementary Table 14.<br />

Discussion<br />

Based on the data obtained from our center, the benefit of early<br />

endoscopy on the outcomes of patients with liver cirrhosis and AVB<br />

could not be supported. It seems to be contrary to the traditional<br />

concept that early endoscopy could achieve more rapid hemostasis<br />

and hence better outcomes. Notably, early endoscopy may influence<br />

basic resuscitation, leading to ischemic complications, and shorten the<br />

duration of action of vasoactive drugs or antibiotics before endoscopic<br />

treatment for acute gastrointestinal bleeding [17]. Additionally, there<br />

were a significantly larger number of patients with active bleeding in<br />

early endoscopy group. Thus, a large amount of blood and contents<br />

in the non-fasting stomach limits the visual field under endoscopy and<br />

masks the primary source of bleeding, thereby increasing the technical<br />

difficulty as well as risk of aspiration or perforation [18]. By comparison,<br />

delayed endoscopy may be safer and provides clearer visual field,<br />

especially after portal pressure has been sufficiently decreased by the<br />

use of vasoactive drugs [10].<br />

Our finding may be influenced by the definition regarding time<br />

to endoscopy, the manifestation of AVB, or the severity of liver<br />

dysfunction. First, until now, any standard definition regarding time<br />

to endoscopy has not been given by any practice guideline yet [2,<br />

3, 6, 19, 20]. Indeed, the definitions regarding time to endoscopy<br />

are heterogeneous among previous studies. By contrast, in the<br />

present study, both of two major definitions, of which one refers to<br />

the interval from the last presentation of gastrointestinal bleeding to<br />

endoscopy [21], and another refers to the interval from the admission<br />

to endoscopy [9, 22], have been employed. It is true that the number<br />

and percentage of patients assigned to early endoscopy group were<br />

different (55 [10.3%] in < 12 h endoscopy group according to the first<br />

definition versus 75 [14.0%] in < 12 h endoscopy group according to<br />

the second definition). On the other hand, the definitions regarding<br />

early endoscopy are also different among previous studies, including <<br />

6h [23], < 12h [21, 22] and < 24h [24]. Accordingly, the results of overall<br />

analyses based on the interval from the last presentation of AVB to<br />

endoscopy are also heterogeneous that < 12 h and < 24 h endoscopy<br />

group, but not < 48 h endoscopy group, had significantly higher inhospital<br />

mortality than delayed endoscopy group.<br />

Second, patients with cirrhosis and AVB who presented with<br />

hematemesis at admission may have worse prognosis than those<br />

who presented with melena [14]. The results of our subgroup analyses<br />

based on the interval from the last presentation of AVB to endoscopy<br />

demonstrated that early endoscopy was significantly associated<br />

with a higher risk of 5-day failure to control bleeding in patients with<br />

hematemesis, but such an association remains in patients with nonhematemesis.<br />

By contrast, a previous cohort study by Chen et al.<br />

found that 6-week rebleeding rate and mortality were lower in patients<br />

with hematemesis who underwent early endoscopy than those<br />

who underwent delayed endoscopy, but not significantly different<br />

between the two groups in patients without hematemesis [22]. Such a<br />

difference between current and previous studies may be because all<br />

of the patients included in the Chen’s study had active AVB, but active<br />

bleeding was observed endoscopically in only 7.4% of our patients.<br />

Rapid control of active bleeding by early endoscopy is beneficial for<br />

preventing from an injury to the liver and other organs and achieving<br />

better outcomes. It can be speculated that patients with hematemesis<br />

without active bleeding will benefit more from delayed endoscopy after<br />

sufficient medical therapy as compared to early endoscopy.<br />

Third, the severity of liver cirrhosis affects the prognosis of AVB [25].<br />

It has been confirmed that MELD score is an independent predictor<br />

for the prognosis of liver cirrhosis with AVB [26, 27]. Huh et al. found<br />

that early endoscopy, which was defined as the interval from the<br />

last presentation of gastrointestinal bleeding to endoscopy ≤ 12 h,<br />

increased the risk of 6-week rebleeding and death in the low-risk<br />

(MELD score ≤ 17) group, but the timing of endoscopy was not<br />

associated with the prognosis in the high-risk (MELD score > 17)<br />

group [21]. By comparison, according to the results of our subgroup<br />

and PSM analyses, the association between timing of endoscopy and<br />

outcomes was not influenced by Child-Pugh class or score. Thus, the<br />

optimal timing of endoscopy may not be dependent upon the severity<br />

of liver cirrhosis.<br />

Our study has several limitations as follows. First, our study was<br />

retrospective. The selection of emergency endoscopy often depends<br />

on the patients’ conditions, physicians’ decisions, and availability<br />

of endoscopists, which leads to a considerable selection bias.<br />

Specifically, patients with massive hematemesis who were not<br />

effectively treated by drugs were more prone to early endoscopy,<br />

those with hemodynamic instability would undergo delayed endoscopy<br />

after basic resuscitation, and those admitted during off-hours might<br />

undergo delayed endoscopy. Although all procedures were performed<br />

by experienced endoscopists, it may be different in judging the<br />

source of gastrointestinal bleeding and treating AVB under endoscopy<br />

among endoscopists, which influences the prognosis of patients. In<br />

addition, endoscopic findings in the stomach were retrospectively<br />

derived from the patients’ medical records alone, but they seemed<br />

to be insufficient to evaluate whether gastric contents had influenced<br />

the efficacy of gastric variceal treatment under endoscopy. Second,<br />

our study excluded patients who had undergone endoscopy at their<br />

local hospitals and outpatient and emergency departments, those<br />

who were not suitable for endoscopy, as well as those who died<br />

before endoscopy. Such patients should be more severe and critical.<br />

Third, this was a single-center study, which should be validated by a<br />

multi-center study. In addition, our study had a relatively small number<br />

of death events, which might be unpowered to achieve statistically<br />

significant results between early and delayed endoscopy groups.<br />

In conclusion, our study did not confirm an association of timing of<br />

endoscopy with risk of 5-day failure to control bleeding or in-hospital<br />

death in patients with cirrhosis and AVB. Endoscopy after adequate<br />

medical therapy may be more effective than urgent endoscopy. RCTs<br />

with strict eligibility criteria and optimal definitions regarding timing of<br />

endoscopy are needed to confirm the effect of the timing of endoscopy<br />

on prognosis of patients with cirrhosis and AVB in the future.<br />

Abbreviations<br />

AASLD American Association for the Study of Liver Diseases<br />

AUGIB Acute upper gastrointestinal bleeding<br />

AVB Acute variceal bleeding<br />

ESGE European Society of Gastrointestinal Endoscopy<br />

HCV Hepatitis C virus<br />

MELD Model for End-stage Liver Disease<br />

PSM Propensity score matching<br />

PT Prothrombin time<br />

RCT Randomized controlled trial<br />

TIPS Trans-jugular intrahepatic portosystemic shunt<br />

Supplementary Information<br />

The online version contains supplementary material available at<br />

https://doi.org/10.1186/s12876-023-02766-8.<br />

Supplementary Material 1<br />

Acknowledgements<br />

We are indebted to our study team for establishing and updating<br />

our retrospective and prospective databases, including Junna Dai,<br />

Cuihong Zhu, Yun Li, Ying Peng, Zheng Ning, Feifei Hou, Jiancheng<br />

Zhao, Han Deng, Ran Wang, Jing Li, Xintong Zhang, Dan Han, Tingxue<br />

Song, Zhong Peng, Wenchun Bao, Jia Zhu, Yingying Li, Zhaohui Bai,<br />

Xiangbo Xu, Qianqian Li, Kexin Zheng, Yang An, Le Wang, Yanyan<br />

Wu, Fangfang Yi, Li Luo, Yue Yin, Shixue Xu, Yiyan Zhang, Min Ding,<br />

Weiwei Wang, Xueying Wang, and Xiaojie Zheng, of whom all had<br />

worked for our study group.<br />

Author Contribution<br />

MP and XQ were involved in the concept and design of study; MP,<br />

ZB, and XQ were involved in the data curation; MP, ZB, DZ, SX, CW,<br />

XG, XS, and XQ were involved in statistical analysis; MP, ZB, and XQ<br />

were involved in drafting the manuscript; all authors were involved<br />

in writing–review and editing; XG, XS, and XQ were involved in the<br />

supervision of study. All authors have made an intellectual contribution<br />

to the manuscript and approved the submission. All authors read and<br />

approved the final manuscript.<br />

Funding<br />

This work was partially supported by the Young and Middle-aged<br />

Scientific and Technological Innovation Talents Support Plan Project of<br />

Shenyang (RC210011).<br />

Data Availability<br />

The dataset data used to support the findings of this study<br />

are available from the corresponding author at email address<br />

upon request.<br />

Declarations<br />

Ethics approval and consent to participate<br />

The study protocol has been approved by the Medical Ethical<br />

Committee of the General Hospital of Northern Theater Command<br />

with an approval number (Y [2022] 019) and performed according to<br />

the Declaration of Helsinki. Medical Ethical Committee of the General<br />

Hospital of Northern Theater Command waived need for written<br />

informed consents due to the retrospective nature of this study.<br />

Consent for publication<br />

Not applicable.<br />

Competing interests<br />

The authors have no conflict of interests related to this publication.<br />

Author details<br />

1<br />

Department of <strong>Gastroenterology</strong>, General Hospital of Northern Theater<br />

Command (formerly General Hospital of Shenyang Military Area), No.<br />

83 Wenhua Road, Shenyang, Liaoning Province 110840, China<br />

GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />

12 13

GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />


2<br />

Postgraduate College, Jinzhou Medical University, Jinzhou, P.R. China<br />

3<br />

Postgraduate College, Shenyang Pharmaceutical University,<br />

Shenyang, P.R. China<br />

4<br />

Department of Internal Medicine, Bezmialem Vakıf University Faculty<br />

of Medicine, İstanbul, Turkey<br />

5<br />

Clinical and Translational Hepatology & Monarch Liver Laboratory,<br />

The Liver Institute, Center of Excellence in Gastrointestinal Sciences,<br />

Rajagiri Hospital, Aluva, Kerala, India<br />

Received: 25 July 2022 / Accepted: 15 April <strong>2023</strong><br />

Published online: 26 June <strong>2023</strong><br />

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md.0000000000002877.<br />

26. Bambha K, Kim WR, Pedersen R, Bida JP, Kremers WK,<br />

Kamath PS. Predictors of early re-bleeding and mortality after<br />

acute variceal haemorrhage in patients with cirrhosis. Gut.<br />

2008;57(6):814–20. https://doi.org/10.1136/gut.2007.137489.<br />

27. Reverter E, Tandon P, Augustin S, Turon F, Casu S, Bastiampillai<br />

R, et al. A MELD-based model to determine risk of mortality<br />

among patients with acute variceal bleeding. <strong>Gastroenterology</strong>.<br />

2014;146(2):412–19.e3. https://doi.org/10.1053/j.<br />

gastro.2013.10.018.<br />

Publisher’s Note<br />

Springer Nature remains neutral with regard to jurisdictional claims in<br />

published maps and institutional affiliations.<br />

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Healthcare practitioners and industry members across the<br />

world are thinking about how to mitigate the environmental<br />

footprint of endoscopy. The modus operandi of the<br />

entire endoscopy patient journey is being scrutinized<br />

from evaluating appropriateness of the procedures, the<br />

endoscopy room environment, the instruments that are<br />

used during clinical procedures, to the equipment that is<br />

employed in the reprocessing room.<br />

The growth in society guidelines and position statements<br />

on green endoscopy underlines this movement well.<br />

For example, the European Society of Gastrointestinal<br />

Endoscopy (ESGE) and European Society of<br />

<strong>Gastroenterology</strong> and Endoscopy Nurses and Associates<br />

(ESGENA) 1 published their position statement on reducing<br />

the environmental footprint of gastrointestinal endoscopy.<br />

The British Society of <strong>Gastroenterology</strong> (BSG), Joint<br />

Accreditation Group (JAG) and Centre for Sustainable<br />

Health (CSH) 2 also published a joint consensus on practical<br />

measures for environmental sustainability in endoscopy.<br />

Prof. Shaji Sebastian, Consultant Gastroenterologist, IBD<br />

Unit, Hull University Teaching Hospitals, is the lead author<br />

Prof. Sebastian discussed how to become sustainable in endoscopy with<br />

Prof. Pohl and Prof. Bisschops, during the PENTAX Medical Hygiene Event.<br />

of the BSG, JAG and CSH joint consensus. We recently<br />

spoke with him about the `sustainable future` of endoscopy<br />

and how to create green endoscopy dream teams.<br />

What measures can endoscopy departments implement<br />

to mitigate their environmental footprints?<br />

There are many ‘low-hanging fruits’ that can minimize a<br />

department’s environmental footprint. One of the most important<br />

aspects is reducing unnecessary procedures, as the biggest<br />

amount of waste in endoscopy is the procedure that was not<br />

needed in the first place. The endoscopy services should have<br />

better vetting procedures to determine the appropriateness of<br />

an endoscopy. Additionally, rationalizing the use of endoscopic<br />

biopsies and where possible using enhanced imaging techniques<br />

to reduce the need for biopsies and adopting resect and discard<br />

policies for diminutive polyps can be incorporated within the<br />

endoscopy departments. One US study, analyzing whether biopsy<br />

pots could be reduced or whether their size could be reduced,<br />

found statistical improvement 3 . As practitioners, we must consider<br />

how we can implement such findings across our endoscopy units.<br />

Ambitious targets are being set by national health services<br />

and ministries. What is essential in achieving this?<br />

It is promising to see regulatory bodies set such ambitious targets.<br />

For example, in the United Kingdom we have committed to net zero<br />

by 2040 (Scope 1 and Scope 2 emissions). I fully embrace these<br />

ambitions, as I believe if we don’t reach for the sky, we won’t get off<br />

the ground. The only way we will achieve this is by working together.<br />

We must collectively find sustainable alternatives that reduce the<br />

impact of our endoscopic procedures.<br />

Alongside this, practitioners must provide regulatory bodies with<br />

information and guidance. We must publish practical guidelines,<br />

even in areas where it may be difficult to obtain such evidence.<br />

Think of infection risks, for example. These vary on a case-by-case<br />

basis, which makes it difficult to establish significant findings. As<br />

1<br />

de Santiago ER, Dinis-Ribeiro M, Pohl H, et al. Reducing the environmental footprint of gastrointestinal endoscopy: European Society of gastrointestinal endoscopy<br />

(ESGE) and European Society of gastroenterology and endoscopy nurses and associates (ESGENA) position statement. Endoscopy. 2022;54(08):797-826.<br />

2<br />

Sebastian S, Dhar A, Baddeley R, et al. Green endoscopy: British Society of <strong>Gastroenterology</strong> (BSG), Joint Accreditation Group (JAG) and Centre for<br />

physicians, and reprocessing nurses, we must provide policymakers<br />

with the right clinical evidence, so their legal expertise can guide us<br />

towards the right decisions.<br />

16 Sustainable Health (CSH) joint consensus on practical measures for environmental sustainability in endoscopy. Gut. <strong>2023</strong>;72(1):12-26.<br />

17<br />

3<br />

Gordon IO, Sherman JD, Leapman, M, et al. Life Cycle Greenhouse Gas Emissions of Gastrointestinal Biopsies in a Surgical Pathology Laboratory.<br />

American Journal of Clinical Pathology. 2021; 156(4): 540-549.<br />

Prof. Shaji Sebastian, Consultant<br />

Gastroenterologist, IBD Unit, Hull<br />

University Teaching Hospitals<br />

Listen to the full dialogue:<br />

Patients must be involved in this<br />

as well. We see that they are<br />

becoming more environmentally<br />

aware and weighing up the<br />

impacts of specific interventions.<br />

Sometimes they are even okay<br />

with trading off some of their<br />

comfort, for example by using<br />

slightly less nitrous oxide during<br />

procedures. More and more<br />

of these patients will enter our<br />

hospital doors, and we must<br />

involve them as informed partners<br />

in decision-making.<br />

Industry has a key role to play too mainly working with researchers<br />

and endoscopy teams to come up with products and solutions<br />

which are not only advancing the applications of endoscopy for<br />

clinical care but also those that will support our green initiatives.<br />

How can the field move forward as one?<br />

A cultural change is happening as endoscopic units are<br />

transforming themselves into green endoscopy dream teams.<br />

Companies, such as PENTAX Medical, have sustainability high on<br />

their agenda and are looking to minimize the environmental impact<br />

of their solutions. Holistic thinking is being applied that spans from<br />

supply chain to waste generation considerations, new society<br />

guidelines that are being published and sustainable product design<br />

principles that are being implemented.<br />

Ultimately endoscopy needs to reinvent itself. We simply cannot<br />

go back to business as usual; we need to be part of the solution,<br />

not the problem. The key is for practitioners and industry to<br />

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environmental sustainability. Pictures of our beautiful planet must<br />

be kept in mind during these discussions, and together we must<br />

act in the long-term interest of our children and future generations.<br />

This is why we should care about green endoscopy.<br />

The endoscopic field is embarking on a steadfast<br />

sustainability transformation journey, whereby<br />

systems-level thinking is prioritized. The entire<br />

product development cycle is being reevaluated<br />

and all aspects – from device design, to materials,<br />

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AND HFE P.C282Y/P.C282Y<br />

James C. Barton 1,2*† , J. Clayborn Barton 2† and Ronald T. Acton 2,3†<br />

Barton et al. BMC <strong>Gastroenterology</strong> (<strong>2023</strong>) 23:137 https://doi.org/10.1186/s12876-023-02763-x<br />


Abstract<br />

Background The aim of this study was to identify characteristics<br />

of non-alcoholic fatty liver disease (NAFLD) in adults<br />

with HFE p.C282Y/p.C282Y.<br />

Methods We retrospectively studied non-Hispanic white<br />

hemochromatosis probands with iron overload (serum ferritin (SF) ><br />

300 μg/L (M), > 200 μg/L (F)) and p.C282Y/p.C282Y at non-screening<br />

diagnosis who did not report alcohol consumption > 14 g/d, have<br />

cirrhosis or other non-NAFLD liver disorders, use steatogenic<br />

medication, or have diagnoses of heritable disorders that increase<br />

NAFLD risk. We identified NAFLD-associated characteristics using<br />

univariate and multivariable analyses.<br />

Results There were 66 probands (31 men, 35 women), mean age<br />

49 ± 14 (SD) y, of whom 16 (24.2%) had NAFLD. The following<br />

characteristics were higher in probands with NAFLD: median SF<br />

(1118 μg/L (range 259, 2663) vs. 567 μg/L (247, 2385); p = 0.0192);<br />

prevalence of elevated ALT/AST (alanine/aspartate aminotransferase)<br />

(43.8% vs. 10.0%; p = 0.0056); and prevalence of type 2 diabetes<br />

(T2DM) (31.3% vs. 10.0%; p = 0.0427). Mean age, sex, and prevalences<br />

of human leukocyte antigen-A*03 positivity, body mass index ≥ 30.0<br />

kg/m 2 , hyperlipidemia, hypertension, and metabolic syndrome in<br />

probands with/without NAFLD did not differ significantly. Logistic<br />

regression on NAFLD using variables SF, elevated ALT/AST, and T2DM<br />

revealed: SF (p = 0.0318; odds ratio 1.0–1.0) and T2DM (p = 0.0342;<br />

1.1–22.3). Median iron removed to achieve iron depletion (QFe) in<br />

probands with/without NAFLD did not differ significantly (3.6 g (1.4–7.2<br />

g) vs. 2.8 g (0.7–11.0 g), respectively; p = 0.6862).<br />

Conclusions NAFLD in hemochromatosis probands with p.C282Y/p.<br />

C282Y is associated with higher median SF and greater T2DM<br />

†<br />

James C. Barton, J. Clayborn Barton and Ronald T. Acton contributed equally to this work.<br />

*Correspondence:<br />

James C. Barton<br />

bartonjames336@gmail.com<br />

1<br />

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA<br />

2<br />

Southern Iron Disorders Center, Birmingham, AL, USA<br />

3<br />

Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA<br />

prevalence, after adjustment for other factors. NAFLD does not<br />

influence QFe significantly.<br />

Keywords Alanine aminotransferase, Aspartate aminotransferase,<br />

Metabolic syndrome, Obesity, Serum ferritin, Type 2 diabetes<br />

Background<br />

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver<br />

abnormalities characterized by steatosis (lipidfilled vacuoles in<br />

hepatocytes), steatohepatitis (steatosis and hepatocyte “ballooning”<br />

with inflammation and necrosis), fibrosis, and cirrhosis [1, 2]. It has<br />

been estimated that 25.2% (95% confidence interval (CI) [22.1, 28.7]) of<br />

persons world-wide have NAFLD [2]. In a metaanalysis of 34 studies,<br />

the prevalence of NAFLD in U.S. whites was 14.4% (95% CI [14.0, 14.8])<br />

[3]. Co-morbid conditions associated with NAFLD include obesity,<br />

type 2 diabetes (T2DM), hyperlipidemia, hypertension, and metabolic<br />

syndrome (MetS) [2].<br />

Hemochromatosis in whites of western European descent is<br />

associated with homozygosity for HFE p.C282Y (rs1800562),<br />

a common missense allele of the homeostatic iron regulator<br />

(chromosome 6p22.2) in linkage disequilibrium with human<br />

leukocyte antigen (HLA)-A*03 [4, 5]. HFE, a non-classical class I<br />

major histocompatibility complex protein, is an upstream regulator<br />

of hepcidin and thus of iron homeostasis [6]. Laboratory phenotypes<br />

of many adults at diagnosis of hemochromatosis and p.C282Y/p.<br />

C282Y include elevated levels of transferrin saturation (TS) and serum<br />

ferritin (SF) [7]. Adults with p.C282Y/p.C282Y have increased risks to<br />

develop iron overload. Severe iron overload occurs predominantly in<br />

men [7, 8]. Non-HFE heritable and environmental variables modify iron<br />

loading in adults with hemochromatosis [5, 7, 9, 10]. Some adults with<br />

p.C282Y/p.C282Y also have hemochromatosis arthropathy, diabetes<br />

mellitus, hypogonadotropic hypogonadism, hepatic cirrhosis, or<br />

cardiomyopathy [7].<br />


GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />


The aim of this study was to identify characteristics of non-alcoholic<br />

fatty liver disease (NAFLD) in adults with HFE p.C282Y/p.C282Y.<br />

We performed a retrospective study of clinical and laboratory<br />

characteristics of unrelated non-Hispanic white adults with<br />

hemochromatosis, iron overload, and p.C282Y/p.C282Y at nonscreening<br />

diagnosis. The present probands, with or without NAFLD,<br />

did not report alcohol consumption > 14 g/d, have other liver disorders,<br />

report using steatogenic medication, or have diagnoses of heritable<br />

disorders that increase NAFLD risk. We identified significant NAFLDassociated<br />

characteristics using univariate and multivariable analyses.<br />

We discuss our findings in the context of previous observations of<br />

co-morbid conditions associated with NAFLD in adults who were and<br />

were not selected for HFE genotypes.<br />

Methods<br />

Subjects included<br />

We compiled data on consecutive self-identified non-Hispanic whites<br />

aged ≥ 18 y referred to an Alabama tertiary hematology center<br />

(1989–2005) for evaluation and management of hemochromatosis<br />

who met the following criteria: (a) had HFE p.C282Y/p.C282Y, (b)<br />

had iron overload defined as serum ferritin (SF) > 300 μg/L (M)<br />

or > 200 μg/L (F) [11, 12], (c) underwent HLA-A typing, (d) had no<br />

known cause of secondary iron overload, (e) started and achieved<br />

iron depletion with therapeutic phlebotomy at this center, and (f)<br />

were the first in their respective families to be diagnosed to have<br />

hemochromatosis (probands).<br />

Medical histories were taken from probands and records of referring<br />

physicians. Referring physicians diagnosed and treated probands<br />

with diabetes, hypertension, and hyperlipidemia. Physicians in the<br />

present hematology center evaluated probands for hemochromatosis<br />

arthropathy, hypogonadotropic hypogonadism, cirrhosis, and<br />

cardiomyopathy, as appropriate. All probands underwent medication<br />

review, physical examination, laboratory testing, imaging procedures,<br />

and evaluation of liver and other conditions, as indicated, before<br />

therapeutic phlebotomy was initiated.<br />

Subjects excluded<br />

We excluded probands with any of the following: (a) diagnosis of<br />

hyperferritinemia, hemochromatosis, or HFE p.C282Y/p.C282Y<br />

in family or population screening, (b) diagnosis of any primary or<br />

secondary hematologic disorder, (c) report of alcohol consumption<br />

> 14 g/d drinkequivalent [13], (d) use of steatogenic medication(s)<br />

[14], (e) diagnosis of a heritable disorder that increases NAFLD risk<br />

[15, 16], (f) volunteer whole-blood donation > two units in the year<br />

before hemochromatosis diagnosis, (g) bariatric operations [17], (h)<br />

viral hepatitis B or C infection, (i) hepatic transient fibroelastography<br />

(FibroScan ® , Echosens, Waltham, MA, USA) suggestive of severe<br />

hepatic fibrosis (≥ 9.4 kilopascals) or cirrhosis (≥ 11.0 kilopascals), (j)<br />

biopsy-proven cirrhosis, k) liver transplant, l) diagnosis of malignancy,<br />

m) anti-cancer therapy, n) chronic inflammatory conditions, or o)<br />

selfreported pregnancy.<br />

Laboratory<br />

Blood specimens were collected during mornings without regard<br />

to fasting. TS and SF were measured using standard methods<br />

(Laboratory Corporation of America, Burlington, NC, USA). We defined<br />

these TS and SF phenotypes to be elevated: TS > 50% (men) and TS<br />

> 45% (women); and SF > 300 μg/L (men) and SF > 200 μg/L (women)<br />

[11, 12].<br />

Serum alanine aminotransferase (ALT) and aspartate aminotransferase<br />

(AST) were measured using standard methods (Laboratory<br />

Corporation of America, Burlington, NC, USA). We defined upper limits<br />

of normal for ALT and AST as > 40 IU/L, respectively. We created<br />

a single dichotomous variable representing either elevated ALT or<br />

elevated AST (elevated ALT/AST).<br />

HFE allele analyses were performed as previously described [18].<br />

We demonstrated HFE p.C282Y homozygosity in 1996 or later in all<br />

probands regardless of dates of diagnoses. We defined HLA-A*03 as<br />

the marker of the hemochromatosis ancestral haplotype [18]. Positivity<br />

for A*03 was defined as A*03 homozygosity or heterozygosity.<br />

Liver biopsy<br />

We recommended that probands undergo percutaneous liver<br />

biopsy (or not) in accordance with hemochromatosis diagnosis and<br />

management guidelines of the American Association for the Study of<br />

Liver Diseases [19].<br />

Diagnosis of non-alcoholic fatty liver disease<br />

We diagnosed NAFLD according to the Practice Guideline of the<br />

American Association for the Study of Liver Diseases, American<br />

College of <strong>Gastroenterology</strong>, and the American Gastroenterological<br />

Association [20]. Diagnostic criterion was steatosis detected either<br />

by interpretation of liver biopsy specimens [1, 20], increased hepatic<br />

echogenicity [20, 21], or attenuation difference between liver and<br />

spleen on unenhanced CT scanning images [22], in the absence of<br />

self-report of alcohol consumption > 14 g/d drink-equivalent [13],<br />

cirrhosis or other non-NAFLD liver disorder, use of steatogenic<br />

medication [14], or diagnosis of a heritable disorder associated with<br />

increased NAFLD risk [15, 16].<br />

Definition of fibrosis-four variables and AST-to-platelet<br />

ratio indices<br />

We computed the AST-to-platelet ratio index (APRI) [23] and fibrosisfour<br />

variables (FIB-4) index [24] in all probands. Threshold (or greater)<br />

values of each index are associated with increased risk for advanced<br />

hepatic fibrosis (stage F3, severe fibrosis with architectural distortion<br />

or stage F4, cirrhosis with architectural distortion) [25]. In a previous<br />

study of adults with hemochromatosis, APRI values > 3.25 had a<br />

positive predictive value for cirrhosis of 65% and a specificity of 97%<br />

[26]. FIB-4 index > 1.10 identified adults with HFE p.C282Y/p.C282Y<br />

with advanced fibrosis with 80% sensitivity, 80% specificity, and 81%<br />

accuracy [26].<br />

Definition of iron removed to achieve iron depletion<br />

Iron depletion therapy, defined as the periodic removal of blood to<br />

eliminate storage iron, was performed in all probands as described<br />

elsewhere [27]. Iron depletion therapy was complete when SF was ≤ 20<br />

μg/L [27]. Iron removed by phlebotomy to achieve iron depletion (QFe)<br />

was estimated to be 200 mg Fe per unit of blood (450–500 mL) [27].<br />

Definitions of other conditions<br />

Definitions of hemochromatosis arthropathy, hypogonadotropic<br />

hypogonadism, cirrhosis, and cardiomyopathy are displayed in<br />

Additional file 1 [.docx; Other diagnostic criteria].<br />

We defined obesity as ≥ 30.0 kg/m 2 [28]. We classified diabetes<br />

according to criteria of the American Diabetes Association [29].<br />

We grouped medical histories of essential hypertension or use of<br />

prescription anti-hypertensive drugs in a dichotomous hypertension<br />

variable. We grouped medical histories of hyperlipidemia or<br />

use of prescription lipid-lowering drugs in a dichotomous<br />

hyperlipidemia variable.<br />

We defined metabolic syndrome (MetS) as the concurrence of the<br />

following three attributes: BMI ≥ 30 kg/m 2 ; systolic blood pressure<br />

≥ 130 mm Hg or diastolic blood pressure ≥ 85 mm Hg; and fasting<br />

serum glucose ≥ 100 mg/dL [28, 30, 31]. We grouped positivity for<br />

these three attributes in a dichotomous MetS variable.<br />

Statistics<br />

The dataset for analyses consisted of complete observations at<br />

diagnosis of hemochromatosis, iron overload, and HFE p.C282Y/p.<br />

C282Y in 66 probands. Age, TS, and SF values are displayed to the<br />

nearest integer. Descriptive data are displayed as enumerations,<br />

percentages (with/without 95% CI), means (± 1 standard deviation<br />

(SD)), or medians (range).<br />

Kolmogorov-Smirnov testing demonstrated that age and TS values did<br />

not differ significantly from those which are normally distributed. We<br />

displayed corresponding values as mean ± 1 SD and compared values<br />

using Student’s t test for unpaired data (two-tailed). We displayed other<br />

continuous variables as medians (range) and compared them using<br />

Mann-Whitney U test (twotailed). We compared percentages using<br />

Fisher’s exact test (two-tailed). We did not use a Bonferroni “correction”<br />

for univariate comparisons because many data were not positively<br />

associated and we did not wish to produce “false negative” results [32].<br />

We performed logistic regression on NAFLD by relaxing the “rule” of<br />

ten events per variable [33] and using independent variables identified<br />

in univariate comparisons for which “uncorrected” values of p were ≤<br />

0.1500 (SF, elevated ALT/AST, and T2DM).<br />

We defined p < 0.05 to be significant. We used Excel ® 2000 (Microsoft<br />

Corp., Redmond, WA, USA), GB-Stat ® (v. 10.0, Dynamic Microsystems,<br />

Inc., Silver Spring, MD, USA), and GraphPad Prism 8 ® (2018; GraphPad<br />

Software, San Diego, CA, USA).<br />

Results<br />

General characteristics of probands<br />

There were 31 men (47.0%) and 35 women (53.0%) of mean age 49<br />

± 14 y. NAFLD was diagnosed in 16 probands (24.2%; 95% CI [14.9,<br />

36.6]). All probands underwent one or more imaging procedures that<br />

detect NAFLD [1, 20, 21]. Thirty-five probands (53.0%) underwent liver<br />

biopsy. Of 16 probands with NAFLD, 11 (68.8%) underwent liver biopsy.<br />

Of 50 probands without NAFLD, 24 (48.0%) underwent liver biopsy.<br />

These percentages did not differ significantly (p = 0.1653). Twentyone<br />

probands (31.8%) underwent liver ultrasonography. Percentages of<br />

probands with and without NAFLD evaluated with liver ultrasonography<br />

did not differ significantly (25.0% vs. 34.0%, respectively; p = 0.5562).<br />

Eighteen probands (27.3%) underwent abdominal CT scanning.<br />

Percentages of probands with and without NAFLD evaluated<br />

with liver ultrasonography did not differ significantly<br />

(25.0% vs. 34.0%, respectively; p = 0.5562). Eighteen<br />

probands (27.3%) underwent abdominal FEATURE<br />

CT scanning.<br />

Percentages of probands with and without NAFLD evaluated<br />

with abdominal CT scanning did not differ significantly<br />

(18.8% of probands vs. 30.0%, with and respectively; without NAFLD p = evaluated 0.5245). with Eleven<br />

Percentages<br />

abdominal probands CT (16.7%) scanning did underwent not differ significantly liver evaluations (18.8% vs. 30.0%, with<br />

respectively; two of these p = 0.5245). modalities. Eleven Percentages probands (16.7%) of underwent probands liver with<br />

evaluations and without NAFLD two of these evaluated modalities. with Percentages two modalities of probands did<br />

with not and differ without significantly NAFLD evaluated (25.0% with two vs. modalities 14.0%, did respectively;<br />

not differ<br />

significantly p = 0.4402). (25.0% Two vs. probands 14.0%, respectively; underwent p = 0.4402). fibroelastography<br />

Two probands<br />

underwent as part of fibroelastography experimental or as part pre-marketing of experimental protocols or pre-marketing (n = 2;<br />

protocols<br />

3.0%). Cirrhosis<br />

(n = 2; 3.0%).<br />

was<br />

Cirrhosis<br />

not diagnosed<br />

was not diagnosed<br />

in any proband<br />

in any proband<br />

based<br />

based on clinical, liver on clinical, liver biopsy, or imaging abnormalities.<br />

Three of 16 probands (18.8%) with NAFLD had none of<br />

Three of 16 probands (18.8%) with NAFLD had none of the NAFLD comorbid<br />

conditions we studied. Median SF and prevalences of elevated<br />

the NAFLD co-morbid conditions we studied. Median SF<br />

and prevalences of elevated ALT/AST and T2DM were<br />

ALT/AST and T2DM were greater in probands with than without NAFLD<br />

greater in probands with than without NAFLD (Table 1).<br />

(Table 1).<br />

Table 1 Characteristics of hemochromatosis probands with HFE<br />

p.C282Y/p.C282Y a<br />

Characteristic<br />

Hemochromatosis arthropathy was diagnosed in 24 probands<br />

(36.4%). The prevalence of hemochromatosis arthropathy did not<br />

differ significantly in probands with and without NAFLD (31.3% vs.<br />

38.3%, respectively; p ~ 1.0000). No proband was diagnosed to have<br />

hypogonadotropic hypogonadism, cirrhosis, or cardiomyopathy.<br />

The prevalence of elevated ALT/AST was significantly greater in<br />

probands with than without NAFLD (Table 1). The prevalence of<br />

elevated ALT was greater in probands with than without NAFLD (37.5%<br />

vs. 8.0%, respectively; p = 0.0009). The prevalence of elevated AST<br />

was greater in probands with than without NAFLD (43.8% vs. 4.0%,<br />

respectively; p = 0.0004). Nine of 16 probands with NAFLD (56.3%) did<br />

not have elevated ALT or AST.<br />

NAFLD<br />

(n = 16)<br />

No<br />

NAFLD<br />

(n = 50)<br />

Value<br />

of p<br />

Age at diagnosis, y (± 1 SD) 51 ± 13 49 ± 15 0.6614<br />

Men, % (n) 56.3 (9) 44.0 (22) 0.5659<br />

Mean transferrin saturation, % (± 1 SD) 77 ± 14 83 ± 17 0.1626<br />

Median serum ferritin, µg/L (range) 1118<br />

(259,<br />

2663)<br />

567 (247,<br />

2385)<br />

No proband had APRI > 0.44, although median APRI was greater in<br />

probands with than without NAFLD (0.15 (range 0.07–0.37) vs. 0.10<br />

(range 0.04–0.23); p = 0.0025). Median FIB-4 in probands with and<br />

without NAFLD did not differ significantly (1.10 (range 0.53–3.29) vs.<br />

0.99 (range 0.28–4.99); p = 0.2915). One woman with and another<br />

0.0192<br />

HLA-A*03 positivity, % (n) 75.0 (12) 82.0 (41) 0.7187<br />

Elevated ALT/AST, % (n) 43.8 (7) 10.0 (5) 0.0056<br />

Obesity (BMI ≥ 30.0 kg/m 2 ), % (n) 18.9 (3) 16.0 (8) ~ 1.0000<br />

Diabetes, type 2, % (n) 31.3 (5) 10.0 (5) 0.0427<br />

Hypertension, % (n) 25.0 (4) 18.0 (9) 0.7187<br />

Hyperlipidemia, % (n) 6.3 (1) 12.0 (6) 1.0000<br />

Metabolic syndrome, % (n) 0.0 (0) 4.0 (2) ~ 1.0000<br />

a All observations were recorded at diagnosis. Blood specimens were collected<br />

during mornings without regard to fasting. ALT, alanine aminotransferase; AST,<br />

aspartate aminotransferase; BMI, body mass index; HLA, human leukocyte<br />

antigen; NAFLD, non-alcoholic fatty liver disease; SD, standard deviation. No<br />

proband had hypogonadotropic hypogonadism, cirrhosis, or cardiomyopathy.<br />

respect<br />

NAFLD<br />

No p<br />

was gre<br />

(range<br />

Median<br />

did no<br />

0.99 (r<br />

and an<br />

althoug<br />

reveal c<br />

Co-mor<br />

liver di<br />

The pr<br />

than w<br />

of obe<br />

proban<br />

cantly<br />

Logistic<br />

Logisti<br />

using t<br />

ALT/A<br />

tions:<br />

error 0<br />

1.5973<br />

p = 0.03<br />

NAFLD<br />

(1.094–<br />

Iron rem<br />

Median<br />

not diff<br />

respect<br />

Discus<br />

The p<br />

associa<br />

adults<br />

p.C282<br />

tion > 1<br />

GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />

20 21



GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />

woman without NAFLD had FIB-4 > 3.25, although their respective liver<br />

biopsy specimens did not reveal cirrhosis.<br />

Co-morbid conditions associated with non-alcoholic fatty<br />

liver disease<br />

The prevalence of T2DM was greater in probands with than without<br />

NAFLD (Table 1). Respective prevalences of obesity, hypertension,<br />

hyperlipidemia, and MetS in probands with and without NAFLD did not<br />

differ significantly (Table 1).<br />

Logistic regression on non-alcoholic fatty liver disease<br />

Logistic regression on NAFLD, the dependent variable, using the<br />

qualifying independent variables SF, elevated ALT/AST, and T2DM,<br />

revealed two positive associations: SF (p = 0.0318; beta coefficient<br />

0.0011; standard error 0.0005) and T2DM (p = 0.0342; beta coefficient<br />

1.5973; standard error 0.7543). This regression (ANOVA p = 0.0362)<br />

accounted for 11.6% of the variance of NAFLD. Odds ratios were SF<br />

(1.000-1.002) and T2DM (1.094–22.311).<br />

Iron removed by phlebotomy to achieve depletion<br />

Median QFe in probands with and without NAFLD did not differ<br />

significantly (3.6 g (1.4–7.2) vs. 2.8 g (0.7–11.0), respectively;<br />

p = 0.6862).<br />

Discussion<br />

The present study evaluated clinical and laboratory associations of<br />

NAFLD in a cohort of non-screening adults with hemochromatosis,<br />

iron overload, and HFE p.C282Y/p.C282Y who did not report alcohol<br />

consumption > 14 g/d, have cirrhosis or other liver disorders, report<br />

using steatogenic medication, or have diagnoses of heritable disorders<br />

that increase NAFLD risk. The prevalence of NAFLD in the present<br />

cohort was 24.2% (95% CI [14.9, 36.6]). In a meta-analysis of 43<br />

studies with 5,758 NAFLD cases and 14,741 controls from diverse<br />

geographic regions, “a significantly increased risk of NAFLD was<br />

observed for the C282Y polymorphism in the Caucasian population<br />

under all genetic models [34].“ In the same meta-analysis, NAFLD risk<br />

in adults with p.C282Y/p.C282Y and adults with wt/wt (absence of<br />

p.C282Y and p.H63D (rs1799945)) did not differ significantly [34].<br />

Median SF was almost two-fold greater in the present probands with<br />

than without NAFLD. In patients with hemochromatosis and HFE<br />

p.C282Y homozygosity, there was is a significant positive correlation<br />

of phlebotomy-mobilized iron with hepatic iron concentration [35],<br />

although QFe in the present study did not differ significantly in<br />

probands with and without NAFLD. In another study, median SF level<br />

but not hepatic iron concentration was significantly higher in p.C282Y<br />

homozygotes with than without hepatic steatosis [36]. Together,<br />

these observations indicate that NAFLD contributes significantly to<br />

hyperferritinemia but not iron overload in p.C282Y homozygotes.<br />

Prevalences of elevated ALT and elevated AST were greater in the<br />

present probands with than without NAFLD, although 56.3% of<br />

probands with NAFLD had neither elevated ALT nor elevated AST,<br />

and elevated ALT/AST was not significantly associated with NAFLD<br />

in a logistic regression. In a meta-analysis of 11 studies of patients<br />

unselected for HFE genotypes, 25% of patients with NAFLD and 19%<br />

of patients with non-alcoholic steatohepatitis had ALT values within<br />

the reference range [37]. These observations suggest that evaluation<br />

for NAFLD should be considered at diagnosis in all subjects with<br />

hemochromatosis and HFE p.C282Y/p.C282Y, regardless of ALT and<br />

AST levels, although current guidelines for hemochromatosis diagnosis<br />

and management do not recommend evaluation for NAFLD in all<br />

patients with or suspected to have hemochromatosis [19].<br />

The prevalence of obesity (BMI ≥ 30 kg/m 2 ) in the present cohort<br />

(15.2% (95% CI [7.9–26.6]) did not differ significantly in probands with<br />

and without NAFLD. We found no reports of the prevalence of obesity<br />

in screening programs that evaluated participants with HFE p.C282Y/p.<br />

C282Y. It is estimated that the worldwide prevalence of obesity in<br />

subjects with NAFLD is ~ 51% [2].<br />

In a Utah study [38], white men with HFE p.C282Y/p.C282Y aged ≥<br />

40 y had significantly lower mean BMI (26.7 ± 0.5 kg/m 2 ) than control<br />

siblings without p.C282Y/p.C282Y (30.5 ± 1.6 kg/m 2 ) and male 1999–<br />

2002 National Health and Nutrition Examination Survey participants<br />

(28.7 ± 0.3 kg/m 2 ) [38]. Corresponding comparisons in women were<br />

not significant [38]. In a U.S. atherosclerosis risk screening program,<br />

median BMI did not differ significantly in 44 white participants with<br />

p.C282Y/p.C282Y (26.5 kg/m 2 (standard error (SE) 0.1)) and 6768 white<br />

participants with wt/wt (26.9 kg/m 2 (SE 0.1)) [39]. Thus, it is uncertain<br />

whether BMI in adults with p.C282Y/p.C282Y differs from that in adults<br />

in the general U.S. population.<br />

Prevalence of T2DM was greater in the present probands with than<br />

without NAFLD. T2DM was also significantly associated with NAFLD,<br />

after adjustment for other variables. These observations suggest<br />

that presence of T2D at diagnosis in hemochromatosis and HFE<br />

p.C282Y/p.C282Y should prompt evaluations for NAFLD. In a study<br />

of 159 non-screening Alabama adult hemochromatosis probands<br />

with HFE p.C282Y/p.C282Y, predictors of T2DM at hemochromatosis<br />

diagnosis were diabetes reports in first-degree family members (odds<br />

ratio 8.5 (95% CI [2.9, 24.8])) and BMI ≥ 30.0 kg/m 2 (odds ratio 1.1<br />

(95% CI [1.0, 1.2])). In another study, NAFLD was also a significant risk<br />

factor for concurrent or future T2DM diagnoses in adults unselected<br />

for HFE genotypes in the general population [40, 41]. Together, these<br />

observations indicate that NAFLD, diabetes reports in firstdegree<br />

family members, and obesity are associated with T2DM in adults with<br />

p.C282Y/p.C282Y.<br />

The prevalence of hypertension in the present cohort was 19.7%<br />

(95% CI [11.3, 31.7]). The prevalence of hypertension in probands with<br />

and without NAFLD did not differ significantly, although NAFLD is a<br />

possible risk factor for hypertension [42, 43]. In studies of Scandinavian<br />

population cohorts, HFE p.C282Y/p.C282Y and extremely elevated TS,<br />

either separately or combined, were associated with increased risk of<br />

anti-hypertension medication use [44].<br />

The prevalence of hyperlipidemia in the present cohort was 10.6%<br />

(95% CI [4.7, 21.2]). The prevalence of hyperlipidemia in the present<br />

probands with and without NAFLD did not differ significantly. In an<br />

atherosclerosis risk screening study, mean low-density lipoprotein<br />

(LDL) cholesterol was lower in participants with HFE p.C282Y/p.C282Y<br />

than wt/wt [39]. In a primary carebased hemochromatosis and iron<br />

overload screening study, participants with p.C282Y/p.C282Y had<br />

lower total and LDL cholesterol levels than participants with wt/wt<br />

[45]. It has been postulated that lower LDL cholesterol in adults with<br />

p.C282Y/p.C282Y is an effect of excess iron on cholesterol metabolism<br />

and lipoprotein formation in the liver [39]. Triglyceride levels in subjects<br />

with p.C282Y/p.C282Y and wt/wt in two population screening<br />

programs did not differ significantly [39, 45].<br />

MetS was uncommon in the present cohort (3.0% (95% CI [0.5,<br />

11.5])) and the prevalence of MetS in probands with and without<br />

NAFLD did not differ significantly. In a post-screening evaluation of<br />

248 participants with HFE p.C282Y/p.C282Y, the prevalence of MetS<br />

was also relatively low 7.3% (95% CI [4.5, 11.4]) [46]. We attribute the<br />

relatively low prevalence of MetS in the present cohort to relatively low<br />

prevalences of obesity, hypertension, and hyperlipidemia.<br />

Probands with cirrhosis were excluded from the present study,<br />

although < 8% of adults with HFE p.C282Y/p.C282Y diagnosed in<br />

either screening or non-screening cohorts published in the 21st<br />

century have cirrhosis [47]. In a multi-institutional study, cirrhosis in<br />

patients with p.C282Y/p.C282Y was significantly associated with age,<br />

diabetes, daily alcohol intake, and iron removed by phlebotomy, taking<br />

into account the effect of other variables, although the prevalence of<br />

fatty liver/steatosis did not differ significantly in 86 adults with and 282<br />

adults without cirrhosis (27.4% and 33.0%, respectively; p = 0.4400)<br />

[8]. In a large study of healthcare records in UK, Netherlands, Italy and<br />

Spain, the hazard ratio for cirrhosis in patients with NAFLD was 4.73<br />

(95% CI [2.43, 9.19]), although the strongest independent predictor of<br />

cirrhosis was a baseline diagnosis of diabetes [48]. In a study that did<br />

not include subjects with p.C282Y/p.C282Y, SF, age, BMI, and diabetes<br />

were independent predictors of histologic severity and advanced<br />

fibrosis in patients with NAFLD [49]. Together, these observations<br />

suggest that age and diabetes are greater risk factors for cirrhosis in<br />

adults with p.C282Y/p.C282Y than NAFLD.<br />

In summary, the percentage of the present hemochromatosis<br />

probands with NAFLD (24.2%; 95% CI [14.9, 36.6]) was higher than<br />

that of whites in general U.S. populations (14.4%; 95% CI [14.0, 14.8])<br />

[3]. In a metaanalysis of global populations, co-morbid conditions<br />

associated with NAFLD included obesity, T2DM, hyperlipidemia,<br />

hypertension, and MetS [2], whereas T2D alone was significantly<br />

associated with NAFLD in the present hemochromatosis probands.<br />

Referring physicians diagnosed and treated the present probands with<br />

diabetes, hypertension, and hyperlipidemia and thus their evaluations<br />

and diagnostic criteria for these disorders may differ from those of<br />

large population studies. LDL cholesterol [39, 45] and total cholesterol<br />

[45] levels are lower in adults with HFE p.C282Y/p.C282Y than wt/<br />

wt. These factors could account in part for the absence of NAFLD<br />

risk factors we studied in 18.8% of the present probands. It is also<br />

plausible that probands without NAFLD risk factors we studied have<br />

other undiagnosed or undocumented conditions that increase NAFLD<br />

risk, including obstructive sleep apnea [50], hypothyroidism [51, 52],<br />

hypopituitarism [53], or heritable disorder(s) [15, 16].<br />

A strength of the present study is analyses based on observations<br />

of non-screening adults with hemochromatosis, iron overload, and<br />

HFE p.C282Y/p.C282Y, with or without NAFLD, who did not report<br />

alcohol consumption > 14 g/d, have cirrhosis or other liver disorders,<br />

report using steatogenic medication, or have diagnoses of heritable<br />

disorders that increase NAFLD risk. The present study does not<br />

permit a comparison of the sensitivity and specificity of liver biopsy,<br />

ultrasonography, and CT scanning in diagnosing NAFLD. It is also<br />

plausible that the lack of significant difference of the prevalence of<br />

NAFLD co-morbid factors other than T2DM we studied between<br />

probands with and without NAFLD may in part reflect type 2 statistical<br />

error(s). Evaluating subgroups of probands with NAFLD based on ALT/<br />

AST values or liver morphology [2] or alcoholic/non-alcoholic fatty liver<br />

scores/indices, detecting alleles associated with increased NAFLD<br />

risk [15, 16], determining the effects of therapeutic phlebotomy on<br />

ALT and AST levels, treating NAFLD, and evaluating of post-diagnosis<br />

observations other than QFe were beyond the scope of this work.<br />

Conclusions<br />

We conclude that NAFLD in hemochromatosis probands with iron<br />

overload and HFE p.C282Y/p.C282Y is associated with higher median<br />

SF and greater T2DM prevalence, after adjustment for other factors.<br />

NAFLD does not influence QFe significantly.<br />

List of abbreviations<br />

ALD alcoholic liver disease<br />

ALT alanine aminotransferase<br />

ANI alcoholic liver disease/non-alcoholic fatty liver disease index<br />

APRI AST-to-platelet ratio index<br />

AST aspartate aminotransferase<br />

BMI body mass index<br />

CI confidence interval<br />

FIB-4 fibrosis-four variables<br />

HFE homeostatic iron regulator gene<br />

HLA human leukocyte antigen<br />

LDL low-density lipoprotein<br />

MetS metabolic syndrome<br />

NAFLD non-alcoholic fatty liver disease<br />

QFe quantity of iron removed by phlebotomy to achieve iron depletion<br />

SD standard deviation<br />

SE standard error<br />

SF serum ferritin<br />

T2DM type 2 diabetes mellitus<br />

TS transferrin saturation<br />

Supplementary Information<br />

The online version contains supplementary material available at<br />

https://doi.org/10.1186/s12876-023-02763-x.<br />

Supplementary Material 1. Definitions of other conditions<br />

Acknowledgements<br />

Not applicable.<br />

Author contributions<br />

JaCB evaluated probands, conceived this study and its methodology,<br />

curated data, performed analyses, and drafted the manuscript. JClB<br />

conceived study methodology, curated data, performed analyses, and<br />

drafted the manuscript. RTA conceived this study and its methodology,<br />

performed analyses, and drafted the manuscript. Each author<br />

approved the manuscript in its final form.<br />

Funding<br />

The authors received no specific funding for this work.<br />

GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />

22 23



GASTROENTEROLOGY TODAY – WINTER <strong>2023</strong><br />

Data Availability<br />

The dataset generated and/or analysed during the current study is<br />

available in the Open Science Framework repository (https://osf.io/<br />

j5gsp/). Data were compiled and displayed in a manner that maintains<br />

proband anonymity. Definitions of hemochromatosis arthropathy,<br />

hypogonadotropic hypogonadism, cirrhosis, and cardiomyopathy are<br />

displayed in Additional file 1 [.docx; Other diagnostic criteria].<br />

Declarations<br />

Ethics approval and consent to participate<br />

This work was performed according to the principles of the Declaration<br />

of Helsinki [43]. Performance of this study was approved by Western<br />

Institutional Review Board, Inc. (submission 2539985–44189619).<br />

The need for obtaining informed consent from participants in this<br />

study was waived by Western Institutional Review Board under United<br />

States Department of Health and Human Services, Office for Human<br />

Research Participants, regulation 45 CFR 46.101(b)(4).<br />

Consent for publication<br />

Not applicable.<br />

Competing interests<br />

None of the authors has a conflict of interest to report.<br />

Received: 13 January <strong>2023</strong> / Accepted: 11 April <strong>2023</strong><br />

Published online: 28 April <strong>2023</strong><br />

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of histologic severity and advanced fibrosis in patients with<br />

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