Gastroenterology Today Winter 2023

Volume 34 No. 4 Winter 2023

CONTENTS 

CONTENTS 

Gastroenterology Today 

4 EDITOR’S COMMENT 

7 FEATURE Timing of endoscopy in patients with cirrhosis 

and acute variceal bleeding: a single-center 

retrospective study 

19 FEATURE Non-alcoholic fatty liver disease in 

hemochromatosis probands with iron 

overload and HFE p.C282Y/p.C282Y 

26 COMPANY NEWS 

This issue edited by: 

Aaron Bhakta 

c/o Media Publishing Company 

Greenoaks, Lockhill 

Upper Sapey, Worcester, WR6 6XR 

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References: 

1. NHS Inform. Constipation. Nov 2023. Available online at: 

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

1,older%20adults%20and%20during%20pregnancy. Accessed Nov 2023. 

2. NICE. Scenario: Constipation in adults. 2023. Available at: 

https://cks.nice.org.uk/topics/constipation/management/adults/ Accessed Nov 2023 

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

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

https://doi.org/10.1016/j.biopha.2018.03.023 

GASTROENTEROLOGY TODAY – WINTER 2023 

3

EDITOR’S COMMENT 

FEATURE 

EDITOR’S COMMENT 

“Data from the 

British Liver 

Trust shows 

that liver 

disease is the 

only major noncommunicable 

disease in 

the UK where 

death rates 

are rising.” 

Christmas 2023. 

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

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

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

associated complications. 

One such presentation of decompensated cirrhosis is acute variceal bleeding, for which the initial 

management is resuscitation and pharmacological treatment followed by upper endoscopy. A number 

of organisations and societies around the world suggest endoscopy within 12 hours of presentation, but 

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

conclusions. In this edition of Gastroenterology Today we feature a single-centre retrospective study looking 

at this issue. 

Aaron Bhakta 

Stronger Together 

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The unique strength of of our our collective organisation will will continue 

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A A HEALTHIER AND SAFER WORLD. 


Publishers Comment 

On behalf of everyone involved with the publishing of Gastroenterology Today I would like to say a big 

thank you to our contributors for their input and a special thank you to our advertisers as without their 

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

all Gastroenterology Departments and Endoscopy Units. Wishing you all a very happy Christmas and 

prosperous 2024. 

Terry Gardner 

Publisher 

GASTROENTEROLOGY TODAY - SUMMER 2023 

GASTROENTEROLOGY TODAY - SUMMER 2023 

Come join join us us 

at at BSG! 

Stand A26 

The Arena 

4 

12 12 

www.steris.com

FEATURE 

TIMING OF ENDOSCOPY IN PATIENTS 

WITH CIRRHOSIS AND ACUTE VARICEAL 

BLEEDING: A SINGLE-CENTER 

RETROSPECTIVE STUDY 

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

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

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

RESEARCH 

Abstract 

Background The optimal timing of endoscopy in liver cirrhosis 

with acute variceal bleeding (AVB) remains controversial in current 

guidelines and studies. 

Methods Consecutive patients with liver cirrhosis and AVB were 

screened. The timing of endoscopy was calculated from the last 

presentation of AVB or the admission to endoscopy. Early endoscopy 

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

score matching (PSM) analysis was performed. Five-day failure to 

control bleeding and in-hospital mortality were evaluated. 

Results Overall, 534 patients were included. When the timing of 

endoscopy was calculated from the last presentation of AVB, PSM 

analysis demonstrated that the rate of 5-day failure to control bleeding 

was significantly higher in early endoscopy group defined as < 48 

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

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

in-hospital mortality was not significantly different between early and 

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

FEATURE 

Peng et al. BMC Gastroenterology (2023) 23:219 

Page 4 of 9 

FEATURE 

AVB, but not significantly associated with control of bleeding [11]. 

However, multiple factors, including the definition regarding timing of 

endoscopy, presentation of AVB, hemodynamic status, and severity 

of liver disease, could not be sufficiently addressed or adjusted in our 

meta-analysis. 

More recently, a large randomized controlled trial (RCT) did not 

demonstrate any significant difference in 30-day mortality between 

patients with upper gastrointestinal bleeding treated with urgent 

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

findings may not be appropriate for the management of AVB, because 

most patients included in this RCT were noncirrhotic (91.8%), and the 

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

Herein, we conducted a retrospective study to further shed light on 

whether early endoscopy was beneficial for patients with cirrhosis 

and AVB, especially by adjusting for the definitions regarding timing of 

endoscopy and early endoscopy, manifestation of AVB, and severity of 

liver disease. 

Methods 

Outcomes 

Outcomes of interest included 5-day failure to control bleeding and 

in-hospital death. 

Definitions 

Timing of endoscopy was calculated according to the interval from 

the last presentation of AUGIB or the admission to endoscopy. 

Accordingly, eligible patients were divided into early and delayed 

endoscopy groups according to three different intervals, including 

< 12 h versus ≥ 12 h, < 24 h versus ≥ 24 h, and < 48 h versus ≥ 48 h. 

AUGIB was defined as hematemesis or melena within 120 h before 

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

of active bleeding from varices on endoscopy; (2) signs of recent 

bleeding, such as white nipple; or (3) variceal bleeding would also be 

considered, if varices were the only lesion in the stomach, and blood 

was found in the stomach or endoscopy was performed 24 h after 

bleeding [3]. Five-day failure to control bleeding was defined as the 

presence of any of the following within 5 days after endoscopy: (1) 

vomiting fresh blood or aspirating more than 100 ml fresh blood for 

patients with naso-gastric tube placement after 2 h of endoscopy; (2) 

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


Study design 

Patients with liver cirrhosis and AVB were screened from our 

retrospective database of 982 patients with liver cirrhosis and acute 

upper gastrointestinal bleeding (AUGIB) who were consecutively 

admitted to our hospital between January 2010 and June 2014 [13, 14] 

and our prospective database of 346 patients with liver cirrhosis and 

AUGIB who were consecutively admitted to our department between 

December 2014 and January 2022 [15, 16]. Age and comorbidities 

were not limited. 

Exclusion criteria were as follows: (1) patients did not undergo 

endoscopy or those with contraindications for endoscopy; (2) patients 

underwent endoscopy at other hospitals or emergency department or 

outpatient clinics of our hospital; (3) endoscopy was performed beyond 

5 days after the last episode of AUGIB; (4) the timing of endoscopy 

was ambiguous according to the medical records; and (5) the source 

of AUGIB was non-variceal or could not be accurately identified 

according to the medical records or endoscopic reports. 

The study protocol has been approved by the Medical Ethical 

Committee of the General Hospital of Northern Theater Command with 

an approval number (Y [2022] 019) and performed according to the 

Declaration of Helsinki. Written informed consents were waived due to 

the retrospective nature of this study. 

Data collection 

Primary data extracted included age, gender, clinical manifestations, 

etiology of liver disease, presence of hepatocellular carcinoma, 

systolic blood pressure, heart rate, hemoglobin, white blood cell, 

platelet count, albumin, alanine aminotransferase, blood urea nitrogen, 

serum creatinine, sodium, and prothrombin time (PT) at admission. 

Active variceal bleeding on endoscopy, source of variceal bleeding, 

endoscopic variceal therapy, surgery or interventional treatment, Child- 

Pugh score and class, and model for end-stage liver disease (MELD) 

score were also recorded. 

Management of AUGIB 

Generally, the management of AUGIB is in accordance with the current 

practice guideline, which primarily includes fluid resuscitation, blood 

transfusion, pharmacological treatment, and endoscopic treatment 

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

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

were hemodynamically unstable. Pharmacological treatment included 

intravenous vasoactive drugs (terlipressin, somatostatin, or octreotide) 

and highdose proton pump inhibitors. Timing of endoscopy was 

decided at the discretion of attending physicians according to the 

patients’ age, consciousness, comorbidities, and hemodynamics. 

Endoscopic treatment was performed by experienced endoscopists. 

Endoscopic variceal therapy includes endoscopic variceal ligation, 

sclerotherapy, and injection of tissue adhesive. Endoscopic variceal 

ligation was primarily employed for the treatment of acute esophageal 

variceal bleeding, sclerotherapy was considered when ligation was 

technically difficult or active variceal bleeding was observed on 

endoscopy, and injection of tissue adhesive was primarily used for the 

treatment of acute gastric variceal bleeding. Repeat endoscopy was 

often recommended 2–4 weeks after the first endoscopic variceal 

therapy, with additional endoscopic variceal treatment(s), if necessary. 

If endoscopy failed to control bleeding, patients would undergo surgery 

or interventional treatment. 

Statistical analyses 

Continuous variables were presented as mean ± standard deviation 

and median (range), and categorical variables were presented as 

frequency (percentage). The nonparametric Mann-Whitney U test was 

used for continuous variables, and the chi-square test and Fisher’s 

exact test were used for categorical variables to explore the difference 

between early and delayed endoscopy groups. 

Logistic and Cox regression analyses were performed to identify 

whether early endoscopy was an independent predictor of 5-day 

failure to control bleeding or in-hospital death. Odds ratios (ORs) 

Fig. 1 Flowchart of patient selection 

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

P = 0.142). 

In the PSM analysis, 46 patients were matched to each 

group (Supplementary Table 2). There was no significant 

difference in rate of 5-day failure to control bleeding or 

in-hospital mortality between the two groups (Table 2). 

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

endoscopy group was significantly older and had higher 

proportions of HCV infection, hematemesis, systolic 

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

active variceal bleeding on endoscopy and white blood 

cell than delayed endoscopy group (Supplementary 

Table 3). Early endoscopy group had significantly higher 

rate of 5-day failure to control bleeding and in-hospital 

mortality than delayed endoscopy group (Table 2). 

and hazard ratios (HRs) with 95% confidence intervals (CIs) were 

calculated. A 1:1 propensity score matching (PSM) analysis was 

performed by using a matching tolerance of 0.02 and greedymatching 

algorithm without replacement to compare the rate of 5-day failure 

to control bleeding and in-hospital mortality between early and 

delayed endoscopy groups. After PSM, the comparability of baseline 

characteristics between the groups was re-evaluated. Matching 

factors included age, gender, systolic blood pressure < 90mmHg, 

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

hematemesis at admission, active variceal bleeding on endoscopy, and 

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

statistically significant. All statistical analyses were performed with IBM 

SPSS 26.0 (IBM Corp, Armonk, NY, USA). 

Results 

Patients 

Overall, 534 patients with cirrhosis and AVB were included (Fig. 1). 

Patient characteristics were shown in Table 1. The median age was 

Multivariate logistic regression analysis demonstrated 

that the interval from last presentation of AVB to endoscopy 

< 24 h was significantly associated with a higher rate 

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

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

analysis showed that the interval from last presentation 

of AVB to endoscopy < 24 h was not significantly associated 

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

4.860, P = 0.597). 





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

endoscopy group was significantly older and had significantly 

higher proportions of HCV infection, 

55.66 years (range: 6.28–92.31 years), and 376 (70.4%) patients 

were male. Hematemesis at admission in 332 (62.2%) patients. Most 

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

score was 10.51 (range: 6.43–38.01). Active bleeding was observed 

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

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

2.4% (n = 13). The causes of death included massive gastrointestinal 

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

(n = 4), and cardiogenic shock (n = 1). 

Time to endoscopy according to the interval from the last 

presentation of AVB to endoscopy 

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

had significantly higher proportions of hepatitis C virus (HCV) infection 

and systolic blood pressure < 90 mmHg and white blood cell than 

delayed endoscopy group (Supplementary Table 1). Early endoscopy 

group had significantly higher rate of 5-day failure to control bleeding 

and in-hospital mortality than delayed endoscopy group (Table 2). 


8 9


FEATURE 

Page 5 of 9 


Page 6 of 9 

FEATURE 


Table 1 Characteristics of included patients 

Variables No. Pts Mean ± SD or 

Median (Range) or 

Frequency (Percentage) 

Age (years) 534 55.66 (6.28–92.31) 

55.78 ± 11.61 

Male 534 376 (70.4%) 

Etiology of underlying liver diseases 534 

Hepatitis B virus 222 (41.6%) 

Hepatitis C virus 47 (8.8%) 

Alcohol abuse 150 (28.1%) 

Hepatocellular carcinoma 534 48 (9.0%) 

Hematemesis 534 332 (62.2%) 

Hemodynamics 

Heart rate (beats per minute) 534 80.00 (44.00-148.00) 

83.36 ± 13.24 

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

Systolic blood pressure (mmHg) 533 115.00 (75.00-176.00) 

116.07 ± 17.59 

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

Laboratory tests 

Hemoglobin (g/L) 533 73.00 (23.00-158.00) 

77.53 ± 22.51 

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

5.45 ± 3.98 

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

87.44 ± 58.82 

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

25.01 ± 18.35 

Albumin (g/L) 524 30.50 (10.00-50.70) 

30.57 ± 6.53 

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

32.70 ± 58.03 

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

8.95 ± 4.79 

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

69.30 ± 45.29 

Sodium (mmol/L) 524 138.5 (109.2-160.10) 

138.44 ± 4.22 

Prothrombin time (seconds) 510 16.00 (10.50–55.00) 

16.85 ± 4.00 

Child-Pugh score 498 7.00 (5.00–13.00) 

7.47 ± 1.82 

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

MELD score 502 10.51 (6.43–38.01) 

11.92 ± 4.61 

Source of variceal bleeding 519 * 

Esophageal varices (%) 313 (60.3%) 

Gastric varices (%) 77 (14.8%) 

Esophageal and gastric varices (%) 129 (24.9%) 

Active variceal bleeding on endoscopy 528 # 39 (7.4%) 

Endoscopic variceal therapy 534 496 (92.9%) 

Surgery or interventional treatment 534 3 (0.6%) 

Rate of 5-day failure to control bleeding 534 27 (5.1%) 

In-hospital mortality 534 13 (2.4%) 

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 

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

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

Overall analysis 

< 12h ≥ 12h P value < 24h ≥ 24h P value < 48h ≥ 48h P value 

(N = 55) (N = 434) 

(N = 114) (N = 357) 

(N = 226) (N = 242) 

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 

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 

PSM analysis 

hematemesis, systolic blood pressure < 90 mmHg, Child- 

Multivariate logistic regression analysis demonstrated that the interval 

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

white blood cell, and blood urea nitrogen than 

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

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

delayed endoscopy group (Supplementary Table 5). Early 

0.912–9.151; P = 0.071). Multivariate Cox regression analysis showed 

endoscopy group had a significantly higher rate of 5-day 

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

failure to control bleeding than delayed endoscopy group, 

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

but a statistically similar in-hospital mortality (Table 2). 

0.706–11.320, P = 0.142). 



< 48 h was significantly associated with a higher rate 

In the PSM analysis, 46 patients were matched to each group 

(Supplementary Table 2). There was no significant difference in rate of 

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

5-day failure to control bleeding or in-hospital mortality between the 

1.486–11.708; P = 0.007). Cox regression analysis showed 

two groups (Table 2). 


< 48 h was not significantly associated with in-hospital 

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


was significantly older and had higher proportions of HCV infection, 


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

group (Supplementary Table 6). Early endoscopy group 

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

had a significantly higher rate of 5-day failure to control 

cell than delayed endoscopy group (Supplementary Table 3). Early 

bleeding than delayed endoscopy group, but a statistically 

endoscopy group had significantly higher rate of 5-day failure to control 

similar in-hospital mortality (Table 2). 

bleeding and in-hospital mortality than delayed endoscopy group 

(Table 2). 

Time to endoscopy according to the interval from the 

admission to endoscopy 


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

group was significantly older and had significantly 

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

higher proportions of HCV infection, Child-Pugh class 

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

B/C, and active variceal bleeding on endoscopy, white 

analysis showed that the interval from last presentation of AVB to 

blood cell, total bilirubin, blood urea nitrogen, Childendoscopy 

< 24 h was not significantly associated with in-hospital 

Pugh score, and MELD score than delayed endoscopy 

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








< 12h 

(N = 46) 

≥ 12h 

(N = 46) 

P value 

< 24h 

(N = 97) 

≥ 24h 

(N = 97) 

P value 

< 48h 

(N = 165) 

≥ 48h 

(N = 165) 

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 

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 

Abbreviations: AVB, acute variceal bleeding; PSM, propensity score matching 

P value 

Table 3 Outcomes according to the timing of endoscopy defined as the interval from the admission to endoscopy 

Overall analysis 

< 12h ≥ 12h P value < 24h ≥ 24h P value < 48h ≥ 48h P value 

(N = 75) (N = 453) 

(N = 175) (N = 349) 

(N = 289) (N = 236) 



PSM analysis 

< 12h 

(N = 63) 

≥ 12h 

(N = 63) 

P value 

< 24h 

(N = 155) 

≥ 24h 

(N = 155) 

P value 

< 48h 

(N = 199) 

≥ 48h 

(N = 199) 



Abbreviations: PSM, propensity score matching 

P value 



that the interval from admission to endoscopy < 12 h was 

was significantly older and had significantly higher proportions of HCV 

not significantly associated with 5-day failure to control 

infection, hematemesis, systolic blood pressure < 90 mmHg, Childbleeding 

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

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

blood 

Multivariate 

cell, and blood 

Cox 

urea 

regression 

nitrogen than 

analysis 

delayed endoscopy 

showed that 

group 

the 

(Supplementary 

interval from 

Table 

admission 

5). Early 

to 

endoscopy 

endoscopy 

group 

< 

had 

12 h 

a significantly 

was not significantly 

higher rate of 

associated 

5-day failure to 

with 

control 

in-hospital 

bleeding than 

death 

delayed 

(HR 

endoscopy 

= 1.981, 

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


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

the interval 

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

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

3). 

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

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

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

< 

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

Table 9). There was no significant difference 

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

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

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

endoscopy 

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

not significantly associated with 5-day failure to control 

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

to Multivariate endoscopy Cox regression analysis showed that the 

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

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

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

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

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

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

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

two 

< 

groups 

48 h 

(Table 

versus 

3). 

≥ 48 h. In the overall-analysis, early 

endoscopy group was significantly older than delayed 


from admission to endoscopy < 12 h was not significantly associated 


10 11

FEATURE 

FEATURE 


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

3.144; P = 0.836). Multivariate Cox regression analysis showed that 

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

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

P = 0.354). 






was significantly older and had significantly higher proportion of Child- 

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










P = 0.135). 


(Supplementary Table 10). There was no significant difference in rate 

of 5-day failure to control bleeding or in-hospital mortality between the 



was significantly older than delayed endoscopy group (Supplementary 

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

to control bleeding or in-hospital mortality between the two groups 

(Table 3). 







P = 0.529). 


(Supplementary Table 12). There was no significant difference in rate 

of 5-day failure to control bleeding or in-hospital mortality between the 


Subgroup analyses 

Subgroup analyses were performed according to the manifestations 

of AUGIB (hematemesis versus nonhematemesis) and severity of liver 

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

were shown in Supplementary Table 13 and Supplementary Table 14. 

Discussion 

Based on the data obtained from our center, the benefit of early 

endoscopy on the outcomes of patients with liver cirrhosis and AVB 

could not be supported. It seems to be contrary to the traditional 

concept that early endoscopy could achieve more rapid hemostasis 

and hence better outcomes. Notably, early endoscopy may influence 

basic resuscitation, leading to ischemic complications, and shorten the 

duration of action of vasoactive drugs or antibiotics before endoscopic 

treatment for acute gastrointestinal bleeding [17]. Additionally, there 

were a significantly larger number of patients with active bleeding in 

early endoscopy group. Thus, a large amount of blood and contents 

in the non-fasting stomach limits the visual field under endoscopy and 

masks the primary source of bleeding, thereby increasing the technical 

difficulty as well as risk of aspiration or perforation [18]. By comparison, 

delayed endoscopy may be safer and provides clearer visual field, 

especially after portal pressure has been sufficiently decreased by the 

use of vasoactive drugs [10]. 

Our finding may be influenced by the definition regarding time 

to endoscopy, the manifestation of AVB, or the severity of liver 

dysfunction. First, until now, any standard definition regarding time 

to endoscopy has not been given by any practice guideline yet [2, 

3, 6, 19, 20]. Indeed, the definitions regarding time to endoscopy 

are heterogeneous among previous studies. By contrast, in the 

present study, both of two major definitions, of which one refers to 

the interval from the last presentation of gastrointestinal bleeding to 

endoscopy [21], and another refers to the interval from the admission 

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

and percentage of patients assigned to early endoscopy group were 

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

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

the second definition). On the other hand, the definitions regarding 

early endoscopy are also different among previous studies, including < 

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

analyses based on the interval from the last presentation of AVB to 

endoscopy are also heterogeneous that < 12 h and < 24 h endoscopy 

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

mortality than delayed endoscopy group. 

Second, patients with cirrhosis and AVB who presented with 

hematemesis at admission may have worse prognosis than those 

who presented with melena [14]. The results of our subgroup analyses 

based on the interval from the last presentation of AVB to endoscopy 

demonstrated that early endoscopy was significantly associated 

with a higher risk of 5-day failure to control bleeding in patients with 

hematemesis, but such an association remains in patients with nonhematemesis. 

By contrast, a previous cohort study by Chen et al. 

found that 6-week rebleeding rate and mortality were lower in patients 

with hematemesis who underwent early endoscopy than those 

who underwent delayed endoscopy, but not significantly different 

between the two groups in patients without hematemesis [22]. Such a 

difference between current and previous studies may be because all 

of the patients included in the Chen’s study had active AVB, but active 

bleeding was observed endoscopically in only 7.4% of our patients. 

Rapid control of active bleeding by early endoscopy is beneficial for 

preventing from an injury to the liver and other organs and achieving 

better outcomes. It can be speculated that patients with hematemesis 

without active bleeding will benefit more from delayed endoscopy after 

sufficient medical therapy as compared to early endoscopy. 

Third, the severity of liver cirrhosis affects the prognosis of AVB [25]. 

It has been confirmed that MELD score is an independent predictor 

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

that early endoscopy, which was defined as the interval from the 

last presentation of gastrointestinal bleeding to endoscopy ≤ 12 h, 

increased the risk of 6-week rebleeding and death in the low-risk 

(MELD score ≤ 17) group, but the timing of endoscopy was not 

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

group [21]. By comparison, according to the results of our subgroup 

and PSM analyses, the association between timing of endoscopy and 

outcomes was not influenced by Child-Pugh class or score. Thus, the 

optimal timing of endoscopy may not be dependent upon the severity 

of liver cirrhosis. 

Our study has several limitations as follows. First, our study was 

retrospective. The selection of emergency endoscopy often depends 

on the patients’ conditions, physicians’ decisions, and availability 

of endoscopists, which leads to a considerable selection bias. 

Specifically, patients with massive hematemesis who were not 

effectively treated by drugs were more prone to early endoscopy, 

those with hemodynamic instability would undergo delayed endoscopy 

after basic resuscitation, and those admitted during off-hours might 

undergo delayed endoscopy. Although all procedures were performed 

by experienced endoscopists, it may be different in judging the 

source of gastrointestinal bleeding and treating AVB under endoscopy 

among endoscopists, which influences the prognosis of patients. In 

addition, endoscopic findings in the stomach were retrospectively 

derived from the patients’ medical records alone, but they seemed 

to be insufficient to evaluate whether gastric contents had influenced 

the efficacy of gastric variceal treatment under endoscopy. Second, 

our study excluded patients who had undergone endoscopy at their 

local hospitals and outpatient and emergency departments, those 

who were not suitable for endoscopy, as well as those who died 

before endoscopy. Such patients should be more severe and critical. 

Third, this was a single-center study, which should be validated by a 

multi-center study. In addition, our study had a relatively small number 

of death events, which might be unpowered to achieve statistically 

significant results between early and delayed endoscopy groups. 

In conclusion, our study did not confirm an association of timing of 

endoscopy with risk of 5-day failure to control bleeding or in-hospital 

death in patients with cirrhosis and AVB. Endoscopy after adequate 

medical therapy may be more effective than urgent endoscopy. RCTs 

with strict eligibility criteria and optimal definitions regarding timing of 

endoscopy are needed to confirm the effect of the timing of endoscopy 

on prognosis of patients with cirrhosis and AVB in the future. 

Abbreviations 

AASLD American Association for the Study of Liver Diseases 

AUGIB Acute upper gastrointestinal bleeding 

AVB Acute variceal bleeding 

ESGE European Society of Gastrointestinal Endoscopy 

HCV Hepatitis C virus 

MELD Model for End-stage Liver Disease 

PSM Propensity score matching 

PT Prothrombin time 

RCT Randomized controlled trial 

TIPS Trans-jugular intrahepatic portosystemic shunt 

Supplementary Information 

The online version contains supplementary material available at 

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

Supplementary Material 1 

Acknowledgements 

We are indebted to our study team for establishing and updating 

our retrospective and prospective databases, including Junna Dai, 

Cuihong Zhu, Yun Li, Ying Peng, Zheng Ning, Feifei Hou, Jiancheng 

Zhao, Han Deng, Ran Wang, Jing Li, Xintong Zhang, Dan Han, Tingxue 

Song, Zhong Peng, Wenchun Bao, Jia Zhu, Yingying Li, Zhaohui Bai, 

Xiangbo Xu, Qianqian Li, Kexin Zheng, Yang An, Le Wang, Yanyan 

Wu, Fangfang Yi, Li Luo, Yue Yin, Shixue Xu, Yiyan Zhang, Min Ding, 

Weiwei Wang, Xueying Wang, and Xiaojie Zheng, of whom all had 

worked for our study group. 

Author Contribution 

MP and XQ were involved in the concept and design of study; MP, 

ZB, and XQ were involved in the data curation; MP, ZB, DZ, SX, CW, 

XG, XS, and XQ were involved in statistical analysis; MP, ZB, and XQ 

were involved in drafting the manuscript; all authors were involved 

in writing–review and editing; XG, XS, and XQ were involved in the 

supervision of study. All authors have made an intellectual contribution 

to the manuscript and approved the submission. All authors read and 

approved the final manuscript. 

Funding 

This work was partially supported by the Young and Middle-aged 

Scientific and Technological Innovation Talents Support Plan Project of 

Shenyang (RC210011). 

Data Availability 

The dataset data used to support the findings of this study 

are available from the corresponding author at email address 

upon request. 

Declarations 

Ethics approval and consent to participate 

The study protocol has been approved by the Medical Ethical 

Committee of the General Hospital of Northern Theater Command 

with an approval number (Y [2022] 019) and performed according to 

the Declaration of Helsinki. Medical Ethical Committee of the General 

Hospital of Northern Theater Command waived need for written 

informed consents due to the retrospective nature of this study. 

Consent for publication 

Not applicable. 

Competing interests 

The authors have no conflict of interests related to this publication. 

Author details 

1 

Department of Gastroenterology, General Hospital of Northern Theater 

Command (formerly General Hospital of Shenyang Military Area), No. 

83 Wenhua Road, Shenyang, Liaoning Province 110840, China 


12 13


FEATURE 

2 

Postgraduate College, Jinzhou Medical University, Jinzhou, P.R. China 

3 

Postgraduate College, Shenyang Pharmaceutical University, 

Shenyang, P.R. China 

4 

Department of Internal Medicine, Bezmialem Vakıf University Faculty 

of Medicine, İstanbul, Turkey 

5 

Clinical and Translational Hepatology & Monarch Liver Laboratory, 

The Liver Institute, Center of Excellence in Gastrointestinal Sciences, 

Rajagiri Hospital, Aluva, Kerala, India 

Received: 25 July 2022 / Accepted: 15 April 2023 

Published online: 26 June 2023 

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Publisher’s Note 

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BUILDING DREAM 

TEAMS IN GREEN 

ENDOSCOPY 

AN INTERVIEW WITH PROF. SEBASTIAN 

Healthcare practitioners and industry members across the 

world are thinking about how to mitigate the environmental 

footprint of endoscopy. The modus operandi of the 

entire endoscopy patient journey is being scrutinized 

from evaluating appropriateness of the procedures, the 

endoscopy room environment, the instruments that are 

used during clinical procedures, to the equipment that is 

employed in the reprocessing room. 

The growth in society guidelines and position statements 

on green endoscopy underlines this movement well. 

For example, the European Society of Gastrointestinal 

Endoscopy (ESGE) and European Society of 

Gastroenterology and Endoscopy Nurses and Associates 

(ESGENA) 1 published their position statement on reducing 

the environmental footprint of gastrointestinal endoscopy. 

The British Society of Gastroenterology (BSG), Joint 

Accreditation Group (JAG) and Centre for Sustainable 

Health (CSH) 2 also published a joint consensus on practical 

measures for environmental sustainability in endoscopy. 

Prof. Shaji Sebastian, Consultant Gastroenterologist, IBD 

Unit, Hull University Teaching Hospitals, is the lead author 

Prof. Sebastian discussed how to become sustainable in endoscopy with 

Prof. Pohl and Prof. Bisschops, during the PENTAX Medical Hygiene Event. 

of the BSG, JAG and CSH joint consensus. We recently 

spoke with him about the `sustainable future` of endoscopy 

and how to create green endoscopy dream teams. 

What measures can endoscopy departments implement 

to mitigate their environmental footprints? 

There are many ‘low-hanging fruits’ that can minimize a 

department’s environmental footprint. One of the most important 

aspects is reducing unnecessary procedures, as the biggest 

amount of waste in endoscopy is the procedure that was not 

needed in the first place. The endoscopy services should have 

better vetting procedures to determine the appropriateness of 

an endoscopy. Additionally, rationalizing the use of endoscopic 

biopsies and where possible using enhanced imaging techniques 

to reduce the need for biopsies and adopting resect and discard 

policies for diminutive polyps can be incorporated within the 

endoscopy departments. One US study, analyzing whether biopsy 

pots could be reduced or whether their size could be reduced, 

found statistical improvement 3 . As practitioners, we must consider 

how we can implement such findings across our endoscopy units. 

Ambitious targets are being set by national health services 

and ministries. What is essential in achieving this? 

It is promising to see regulatory bodies set such ambitious targets. 

For example, in the United Kingdom we have committed to net zero 

by 2040 (Scope 1 and Scope 2 emissions). I fully embrace these 

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

the ground. The only way we will achieve this is by working together. 

We must collectively find sustainable alternatives that reduce the 

impact of our endoscopic procedures. 

Alongside this, practitioners must provide regulatory bodies with 

information and guidance. We must publish practical guidelines, 

even in areas where it may be difficult to obtain such evidence. 

Think of infection risks, for example. These vary on a case-by-case 

basis, which makes it difficult to establish significant findings. As 

1 

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

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

2 

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

physicians, and reprocessing nurses, we must provide policymakers 

with the right clinical evidence, so their legal expertise can guide us 

towards the right decisions. 

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

17 

3 

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

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

Prof. Shaji Sebastian, Consultant 

Gastroenterologist, IBD Unit, Hull 

University Teaching Hospitals 

Listen to the full dialogue: 

Patients must be involved in this 

as well. We see that they are 

becoming more environmentally 

aware and weighing up the 

impacts of specific interventions. 

Sometimes they are even okay 

with trading off some of their 

comfort, for example by using 

slightly less nitrous oxide during 

procedures. More and more 

of these patients will enter our 

hospital doors, and we must 

involve them as informed partners 

in decision-making. 

Industry has a key role to play too mainly working with researchers 

and endoscopy teams to come up with products and solutions 

which are not only advancing the applications of endoscopy for 

clinical care but also those that will support our green initiatives. 

How can the field move forward as one? 

A cultural change is happening as endoscopic units are 

transforming themselves into green endoscopy dream teams. 

Companies, such as PENTAX Medical, have sustainability high on 

their agenda and are looking to minimize the environmental impact 

of their solutions. Holistic thinking is being applied that spans from 

supply chain to waste generation considerations, new society 

guidelines that are being published and sustainable product design 

principles that are being implemented. 

Ultimately endoscopy needs to reinvent itself. We simply cannot 

go back to business as usual; we need to be part of the solution, 

not the problem. The key is for practitioners and industry to 

work together, find solutions, and collaborate on this journey for 

environmental sustainability. Pictures of our beautiful planet must 

be kept in mind during these discussions, and together we must 

act in the long-term interest of our children and future generations. 

This is why we should care about green endoscopy. 

The endoscopic field is embarking on a steadfast 

sustainability transformation journey, whereby 

systems-level thinking is prioritized. The entire 

product development cycle is being reevaluated 

and all aspects – from device design, to materials, 

distribution and disposal – are being challenged. 

Through innovation and collaboration, medical 

solutions are increasingly coming to fruition that 

minimize the environmental footprint of the field. 

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patient safety and infection prevention in endoscopy. 

The recently launched PENTAX Medical INSPIRA TM 

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NON-ALCOHOLIC FATTY LIVER 

DISEASE IN HEMOCHROMATOSIS 

PROBANDS WITH IRON OVERLOAD 

AND HFE P.C282Y/P.C282Y 

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

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

RESEARCH 

Abstract 

Background The aim of this study was to identify characteristics 

of non-alcoholic fatty liver disease (NAFLD) in adults 

with HFE p.C282Y/p.C282Y. 

Methods We retrospectively studied non-Hispanic white 

hemochromatosis probands with iron overload (serum ferritin (SF) > 

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

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

cirrhosis or other non-NAFLD liver disorders, use steatogenic 

medication, or have diagnoses of heritable disorders that increase 

NAFLD risk. We identified NAFLD-associated characteristics using 

univariate and multivariable analyses. 

Results There were 66 probands (31 men, 35 women), mean age 

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

characteristics were higher in probands with NAFLD: median SF 

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

prevalence of elevated ALT/AST (alanine/aspartate aminotransferase) 

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

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

of human leukocyte antigen-A*03 positivity, body mass index ≥ 30.0 

kg/m 2 , hyperlipidemia, hypertension, and metabolic syndrome in 

probands with/without NAFLD did not differ significantly. Logistic 

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

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

1.1–22.3). Median iron removed to achieve iron depletion (QFe) in 

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

g) vs. 2.8 g (0.7–11.0 g), respectively; p = 0.6862). 

Conclusions NAFLD in hemochromatosis probands with p.C282Y/p. 

C282Y is associated with higher median SF and greater T2DM 

† 

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

*Correspondence: 

James C. Barton 

bartonjames336@gmail.com 

1 

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA 

2 

Southern Iron Disorders Center, Birmingham, AL, USA 

3 

Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA 

prevalence, after adjustment for other factors. NAFLD does not 

influence QFe significantly. 

Keywords Alanine aminotransferase, Aspartate aminotransferase, 

Metabolic syndrome, Obesity, Serum ferritin, Type 2 diabetes 

Background 

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver 

abnormalities characterized by steatosis (lipidfilled vacuoles in 

hepatocytes), steatohepatitis (steatosis and hepatocyte “ballooning” 

with inflammation and necrosis), fibrosis, and cirrhosis [1, 2]. It has 

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

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

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

[3]. Co-morbid conditions associated with NAFLD include obesity, 

type 2 diabetes (T2DM), hyperlipidemia, hypertension, and metabolic 

syndrome (MetS) [2]. 

Hemochromatosis in whites of western European descent is 

associated with homozygosity for HFE p.C282Y (rs1800562), 

a common missense allele of the homeostatic iron regulator 

(chromosome 6p22.2) in linkage disequilibrium with human 

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

major histocompatibility complex protein, is an upstream regulator 

of hepcidin and thus of iron homeostasis [6]. Laboratory phenotypes 

of many adults at diagnosis of hemochromatosis and p.C282Y/p. 

C282Y include elevated levels of transferrin saturation (TS) and serum 

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

develop iron overload. Severe iron overload occurs predominantly in 

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

loading in adults with hemochromatosis [5, 7, 9, 10]. Some adults with 

p.C282Y/p.C282Y also have hemochromatosis arthropathy, diabetes 

mellitus, hypogonadotropic hypogonadism, hepatic cirrhosis, or 

cardiomyopathy [7]. 



FEATURE 

The aim of this study was to identify characteristics of non-alcoholic 

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

We performed a retrospective study of clinical and laboratory 

characteristics of unrelated non-Hispanic white adults with 

hemochromatosis, iron overload, and p.C282Y/p.C282Y at nonscreening 

diagnosis. The present probands, with or without NAFLD, 

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

report using steatogenic medication, or have diagnoses of heritable 

disorders that increase NAFLD risk. We identified significant NAFLDassociated 

characteristics using univariate and multivariable analyses. 

We discuss our findings in the context of previous observations of 

co-morbid conditions associated with NAFLD in adults who were and 

were not selected for HFE genotypes. 

Methods 

Subjects included 

We compiled data on consecutive self-identified non-Hispanic whites 

aged ≥ 18 y referred to an Alabama tertiary hematology center 

(1989–2005) for evaluation and management of hemochromatosis 

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

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

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

known cause of secondary iron overload, (e) started and achieved 

iron depletion with therapeutic phlebotomy at this center, and (f) 

were the first in their respective families to be diagnosed to have 

hemochromatosis (probands). 

Medical histories were taken from probands and records of referring 

physicians. Referring physicians diagnosed and treated probands 

with diabetes, hypertension, and hyperlipidemia. Physicians in the 

present hematology center evaluated probands for hemochromatosis 

arthropathy, hypogonadotropic hypogonadism, cirrhosis, and 

cardiomyopathy, as appropriate. All probands underwent medication 

review, physical examination, laboratory testing, imaging procedures, 

and evaluation of liver and other conditions, as indicated, before 

therapeutic phlebotomy was initiated. 

Subjects excluded 

We excluded probands with any of the following: (a) diagnosis of 

hyperferritinemia, hemochromatosis, or HFE p.C282Y/p.C282Y 

in family or population screening, (b) diagnosis of any primary or 

secondary hematologic disorder, (c) report of alcohol consumption 

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

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

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

before hemochromatosis diagnosis, (g) bariatric operations [17], (h) 

viral hepatitis B or C infection, (i) hepatic transient fibroelastography 

(FibroScan ® , Echosens, Waltham, MA, USA) suggestive of severe 

hepatic fibrosis (≥ 9.4 kilopascals) or cirrhosis (≥ 11.0 kilopascals), (j) 

biopsy-proven cirrhosis, k) liver transplant, l) diagnosis of malignancy, 

m) anti-cancer therapy, n) chronic inflammatory conditions, or o) 

selfreported pregnancy. 

Laboratory 

Blood specimens were collected during mornings without regard 

to fasting. TS and SF were measured using standard methods 

(Laboratory Corporation of America, Burlington, NC, USA). We defined 

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

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

[11, 12]. 

Serum alanine aminotransferase (ALT) and aspartate aminotransferase 

(AST) were measured using standard methods (Laboratory 

Corporation of America, Burlington, NC, USA). We defined upper limits 

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

a single dichotomous variable representing either elevated ALT or 

elevated AST (elevated ALT/AST). 

HFE allele analyses were performed as previously described [18]. 

We demonstrated HFE p.C282Y homozygosity in 1996 or later in all 

probands regardless of dates of diagnoses. We defined HLA-A*03 as 

the marker of the hemochromatosis ancestral haplotype [18]. Positivity 

for A*03 was defined as A*03 homozygosity or heterozygosity. 

Liver biopsy 

We recommended that probands undergo percutaneous liver 

biopsy (or not) in accordance with hemochromatosis diagnosis and 

management guidelines of the American Association for the Study of 

Liver Diseases [19]. 

Diagnosis of non-alcoholic fatty liver disease 

We diagnosed NAFLD according to the Practice Guideline of the 

American Association for the Study of Liver Diseases, American 

College of Gastroenterology, and the American Gastroenterological 

Association [20]. Diagnostic criterion was steatosis detected either 

by interpretation of liver biopsy specimens [1, 20], increased hepatic 

echogenicity [20, 21], or attenuation difference between liver and 

spleen on unenhanced CT scanning images [22], in the absence of 

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

cirrhosis or other non-NAFLD liver disorder, use of steatogenic 

medication [14], or diagnosis of a heritable disorder associated with 

increased NAFLD risk [15, 16]. 

Definition of fibrosis-four variables and AST-to-platelet 

ratio indices 

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

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

values of each index are associated with increased risk for advanced 

hepatic fibrosis (stage F3, severe fibrosis with architectural distortion 

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

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

positive predictive value for cirrhosis of 65% and a specificity of 97% 

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

with advanced fibrosis with 80% sensitivity, 80% specificity, and 81% 

accuracy [26]. 

Definition of iron removed to achieve iron depletion 

Iron depletion therapy, defined as the periodic removal of blood to 

eliminate storage iron, was performed in all probands as described 

elsewhere [27]. Iron depletion therapy was complete when SF was ≤ 20 

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

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

Definitions of other conditions 

Definitions of hemochromatosis arthropathy, hypogonadotropic 

hypogonadism, cirrhosis, and cardiomyopathy are displayed in 

Additional file 1 [.docx; Other diagnostic criteria]. 

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

according to criteria of the American Diabetes Association [29]. 

We grouped medical histories of essential hypertension or use of 

prescription anti-hypertensive drugs in a dichotomous hypertension 

variable. We grouped medical histories of hyperlipidemia or 

use of prescription lipid-lowering drugs in a dichotomous 

hyperlipidemia variable. 

We defined metabolic syndrome (MetS) as the concurrence of the 

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

≥ 130 mm Hg or diastolic blood pressure ≥ 85 mm Hg; and fasting 

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

these three attributes in a dichotomous MetS variable. 

Statistics 

The dataset for analyses consisted of complete observations at 

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

C282Y in 66 probands. Age, TS, and SF values are displayed to the 

nearest integer. Descriptive data are displayed as enumerations, 

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

(SD)), or medians (range). 

Kolmogorov-Smirnov testing demonstrated that age and TS values did 

not differ significantly from those which are normally distributed. We 

displayed corresponding values as mean ± 1 SD and compared values 

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

continuous variables as medians (range) and compared them using 

Mann-Whitney U test (twotailed). We compared percentages using 

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

for univariate comparisons because many data were not positively 

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

We performed logistic regression on NAFLD by relaxing the “rule” of 

ten events per variable [33] and using independent variables identified 

in univariate comparisons for which “uncorrected” values of p were ≤ 

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

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

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

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

Software, San Diego, CA, USA). 

Results 

General characteristics of probands 

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

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

36.6]). All probands underwent one or more imaging procedures that 

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

biopsy. Of 16 probands with NAFLD, 11 (68.8%) underwent liver biopsy. 

Of 50 probands without NAFLD, 24 (48.0%) underwent liver biopsy. 

These percentages did not differ significantly (p = 0.1653). Twentyone 

probands (31.8%) underwent liver ultrasonography. Percentages of 

probands with and without NAFLD evaluated with liver ultrasonography 

did not differ significantly (25.0% vs. 34.0%, respectively; p = 0.5562). 

Eighteen probands (27.3%) underwent abdominal CT scanning. 

Percentages of probands with and without NAFLD evaluated 

with liver ultrasonography did not differ significantly 

(25.0% vs. 34.0%, respectively; p = 0.5562). Eighteen 

probands (27.3%) underwent abdominal FEATURE 

CT scanning. 

Percentages of probands with and without NAFLD evaluated 

with abdominal CT scanning did not differ significantly 

(18.8% of probands vs. 30.0%, with and respectively; without NAFLD p = evaluated 0.5245). with Eleven 

Percentages 

abdominal probands CT (16.7%) scanning did underwent not differ significantly liver evaluations (18.8% vs. 30.0%, with 

respectively; two of these p = 0.5245). modalities. Eleven Percentages probands (16.7%) of underwent probands liver with 

evaluations and without NAFLD two of these evaluated modalities. with Percentages two modalities of probands did 

with not and differ without significantly NAFLD evaluated (25.0% with two vs. modalities 14.0%, did respectively; 

not differ 

significantly p = 0.4402). (25.0% Two vs. probands 14.0%, respectively; underwent p = 0.4402). fibroelastography 

Two probands 

underwent as part of fibroelastography experimental or as part pre-marketing of experimental protocols or pre-marketing (n = 2; 

protocols 

3.0%). Cirrhosis 

(n = 2; 3.0%). 

was 

Cirrhosis 

not diagnosed 

was not diagnosed 

in any proband 

in any proband 

based 

based on clinical, liver on clinical, liver biopsy, or imaging abnormalities. 

Three of 16 probands (18.8%) with NAFLD had none of 

Three of 16 probands (18.8%) with NAFLD had none of the NAFLD comorbid 

conditions we studied. Median SF and prevalences of elevated 

the NAFLD co-morbid conditions we studied. Median SF 

and prevalences of elevated ALT/AST and T2DM were 

ALT/AST and T2DM were greater in probands with than without NAFLD 

greater in probands with than without NAFLD (Table 1). 

(Table 1). 

Table 1 Characteristics of hemochromatosis probands with HFE 

p.C282Y/p.C282Y a 

Characteristic 

Hemochromatosis arthropathy was diagnosed in 24 probands 

(36.4%). The prevalence of hemochromatosis arthropathy did not 

differ significantly in probands with and without NAFLD (31.3% vs. 

38.3%, respectively; p ~ 1.0000). No proband was diagnosed to have 

hypogonadotropic hypogonadism, cirrhosis, or cardiomyopathy. 

The prevalence of elevated ALT/AST was significantly greater in 

probands with than without NAFLD (Table 1). The prevalence of 

elevated ALT was greater in probands with than without NAFLD (37.5% 

vs. 8.0%, respectively; p = 0.0009). The prevalence of elevated AST 

was greater in probands with than without NAFLD (43.8% vs. 4.0%, 

respectively; p = 0.0004). Nine of 16 probands with NAFLD (56.3%) did 

not have elevated ALT or AST. 

NAFLD 

(n = 16) 

No 

NAFLD 

(n = 50) 

Value 

of p 

Age at diagnosis, y (± 1 SD) 51 ± 13 49 ± 15 0.6614 

Men, % (n) 56.3 (9) 44.0 (22) 0.5659 

Mean transferrin saturation, % (± 1 SD) 77 ± 14 83 ± 17 0.1626 

Median serum ferritin, µg/L (range) 1118 

(259, 

2663) 

567 (247, 

2385) 

No proband had APRI > 0.44, although median APRI was greater in 

probands with than without NAFLD (0.15 (range 0.07–0.37) vs. 0.10 

(range 0.04–0.23); p = 0.0025). Median FIB-4 in probands with and 

without NAFLD did not differ significantly (1.10 (range 0.53–3.29) vs. 

0.99 (range 0.28–4.99); p = 0.2915). One woman with and another 

0.0192 

HLA-A*03 positivity, % (n) 75.0 (12) 82.0 (41) 0.7187 

Elevated ALT/AST, % (n) 43.8 (7) 10.0 (5) 0.0056 

Obesity (BMI ≥ 30.0 kg/m 2 ), % (n) 18.9 (3) 16.0 (8) ~ 1.0000 

Diabetes, type 2, % (n) 31.3 (5) 10.0 (5) 0.0427 

Hypertension, % (n) 25.0 (4) 18.0 (9) 0.7187 

Hyperlipidemia, % (n) 6.3 (1) 12.0 (6) 1.0000 

Metabolic syndrome, % (n) 0.0 (0) 4.0 (2) ~ 1.0000 

a All observations were recorded at diagnosis. Blood specimens were collected 

during mornings without regard to fasting. ALT, alanine aminotransferase; AST, 

aspartate aminotransferase; BMI, body mass index; HLA, human leukocyte 

antigen; NAFLD, non-alcoholic fatty liver disease; SD, standard deviation. No 

proband had hypogonadotropic hypogonadism, cirrhosis, or cardiomyopathy. 

respect 

NAFLD 

No p 

was gre 

(range 

Median 

did no 

0.99 (r 

and an 

althoug 

reveal c 

Co-mor 

liver di 

The pr 

than w 

of obe 

proban 

cantly 

Logistic 

Logisti 

using t 

ALT/A 

tions: 

error 0 

1.5973 

p = 0.03 

NAFLD 

(1.094– 

Iron rem 

Median 

not diff 

respect 

Discus 

The p 

associa 

adults 

p.C282 

tion > 1 


20 21

FEATURE 

FEATURE 


woman without NAFLD had FIB-4 > 3.25, although their respective liver 

biopsy specimens did not reveal cirrhosis. 

Co-morbid conditions associated with non-alcoholic fatty 

liver disease 

The prevalence of T2DM was greater in probands with than without 

NAFLD (Table 1). Respective prevalences of obesity, hypertension, 

hyperlipidemia, and MetS in probands with and without NAFLD did not 

differ significantly (Table 1). 

Logistic regression on non-alcoholic fatty liver disease 

Logistic regression on NAFLD, the dependent variable, using the 

qualifying independent variables SF, elevated ALT/AST, and T2DM, 

revealed two positive associations: SF (p = 0.0318; beta coefficient 

0.0011; standard error 0.0005) and T2DM (p = 0.0342; beta coefficient 

1.5973; standard error 0.7543). This regression (ANOVA p = 0.0362) 

accounted for 11.6% of the variance of NAFLD. Odds ratios were SF 

(1.000-1.002) and T2DM (1.094–22.311). 

Iron removed by phlebotomy to achieve depletion 

Median QFe in probands with and without NAFLD did not differ 

significantly (3.6 g (1.4–7.2) vs. 2.8 g (0.7–11.0), respectively; 

p = 0.6862). 

Discussion 

The present study evaluated clinical and laboratory associations of 

NAFLD in a cohort of non-screening adults with hemochromatosis, 

iron overload, and HFE p.C282Y/p.C282Y who did not report alcohol 

consumption > 14 g/d, have cirrhosis or other liver disorders, report 

using steatogenic medication, or have diagnoses of heritable disorders 

that increase NAFLD risk. The prevalence of NAFLD in the present 

cohort was 24.2% (95% CI [14.9, 36.6]). In a meta-analysis of 43 

studies with 5,758 NAFLD cases and 14,741 controls from diverse 

geographic regions, “a significantly increased risk of NAFLD was 

observed for the C282Y polymorphism in the Caucasian population 

under all genetic models [34].“ In the same meta-analysis, NAFLD risk 

in adults with p.C282Y/p.C282Y and adults with wt/wt (absence of 

p.C282Y and p.H63D (rs1799945)) did not differ significantly [34]. 

Median SF was almost two-fold greater in the present probands with 

than without NAFLD. In patients with hemochromatosis and HFE 

p.C282Y homozygosity, there was is a significant positive correlation 

of phlebotomy-mobilized iron with hepatic iron concentration [35], 

although QFe in the present study did not differ significantly in 

probands with and without NAFLD. In another study, median SF level 

but not hepatic iron concentration was significantly higher in p.C282Y 

homozygotes with than without hepatic steatosis [36]. Together, 

these observations indicate that NAFLD contributes significantly to 

hyperferritinemia but not iron overload in p.C282Y homozygotes. 

Prevalences of elevated ALT and elevated AST were greater in the 

present probands with than without NAFLD, although 56.3% of 

probands with NAFLD had neither elevated ALT nor elevated AST, 

and elevated ALT/AST was not significantly associated with NAFLD 

in a logistic regression. In a meta-analysis of 11 studies of patients 

unselected for HFE genotypes, 25% of patients with NAFLD and 19% 

of patients with non-alcoholic steatohepatitis had ALT values within 

the reference range [37]. These observations suggest that evaluation 

for NAFLD should be considered at diagnosis in all subjects with 

hemochromatosis and HFE p.C282Y/p.C282Y, regardless of ALT and 

AST levels, although current guidelines for hemochromatosis diagnosis 

and management do not recommend evaluation for NAFLD in all 

patients with or suspected to have hemochromatosis [19]. 

The prevalence of obesity (BMI ≥ 30 kg/m 2 ) in the present cohort 

(15.2% (95% CI [7.9–26.6]) did not differ significantly in probands with 

and without NAFLD. We found no reports of the prevalence of obesity 

in screening programs that evaluated participants with HFE p.C282Y/p. 

C282Y. It is estimated that the worldwide prevalence of obesity in 

subjects with NAFLD is ~ 51% [2]. 

In a Utah study [38], white men with HFE p.C282Y/p.C282Y aged ≥ 

40 y had significantly lower mean BMI (26.7 ± 0.5 kg/m 2 ) than control 

siblings without p.C282Y/p.C282Y (30.5 ± 1.6 kg/m 2 ) and male 1999– 

2002 National Health and Nutrition Examination Survey participants 

(28.7 ± 0.3 kg/m 2 ) [38]. Corresponding comparisons in women were 

not significant [38]. In a U.S. atherosclerosis risk screening program, 

median BMI did not differ significantly in 44 white participants with 

p.C282Y/p.C282Y (26.5 kg/m 2 (standard error (SE) 0.1)) and 6768 white 

participants with wt/wt (26.9 kg/m 2 (SE 0.1)) [39]. Thus, it is uncertain 

whether BMI in adults with p.C282Y/p.C282Y differs from that in adults 

in the general U.S. population. 

Prevalence of T2DM was greater in the present probands with than 

without NAFLD. T2DM was also significantly associated with NAFLD, 

after adjustment for other variables. These observations suggest 

that presence of T2D at diagnosis in hemochromatosis and HFE 

p.C282Y/p.C282Y should prompt evaluations for NAFLD. In a study 

of 159 non-screening Alabama adult hemochromatosis probands 

with HFE p.C282Y/p.C282Y, predictors of T2DM at hemochromatosis 

diagnosis were diabetes reports in first-degree family members (odds 

ratio 8.5 (95% CI [2.9, 24.8])) and BMI ≥ 30.0 kg/m 2 (odds ratio 1.1 

(95% CI [1.0, 1.2])). In another study, NAFLD was also a significant risk 

factor for concurrent or future T2DM diagnoses in adults unselected 

for HFE genotypes in the general population [40, 41]. Together, these 

observations indicate that NAFLD, diabetes reports in firstdegree 

family members, and obesity are associated with T2DM in adults with 

p.C282Y/p.C282Y. 

The prevalence of hypertension in the present cohort was 19.7% 

(95% CI [11.3, 31.7]). The prevalence of hypertension in probands with 

and without NAFLD did not differ significantly, although NAFLD is a 

possible risk factor for hypertension [42, 43]. In studies of Scandinavian 

population cohorts, HFE p.C282Y/p.C282Y and extremely elevated TS, 

either separately or combined, were associated with increased risk of 

anti-hypertension medication use [44]. 

The prevalence of hyperlipidemia in the present cohort was 10.6% 

(95% CI [4.7, 21.2]). The prevalence of hyperlipidemia in the present 

probands with and without NAFLD did not differ significantly. In an 

atherosclerosis risk screening study, mean low-density lipoprotein 

(LDL) cholesterol was lower in participants with HFE p.C282Y/p.C282Y 

than wt/wt [39]. In a primary carebased hemochromatosis and iron 

overload screening study, participants with p.C282Y/p.C282Y had 

lower total and LDL cholesterol levels than participants with wt/wt 

[45]. It has been postulated that lower LDL cholesterol in adults with 

p.C282Y/p.C282Y is an effect of excess iron on cholesterol metabolism 

and lipoprotein formation in the liver [39]. Triglyceride levels in subjects 

with p.C282Y/p.C282Y and wt/wt in two population screening 

programs did not differ significantly [39, 45]. 

MetS was uncommon in the present cohort (3.0% (95% CI [0.5, 

11.5])) and the prevalence of MetS in probands with and without 

NAFLD did not differ significantly. In a post-screening evaluation of 

248 participants with HFE p.C282Y/p.C282Y, the prevalence of MetS 

was also relatively low 7.3% (95% CI [4.5, 11.4]) [46]. We attribute the 

relatively low prevalence of MetS in the present cohort to relatively low 

prevalences of obesity, hypertension, and hyperlipidemia. 

Probands with cirrhosis were excluded from the present study, 

although < 8% of adults with HFE p.C282Y/p.C282Y diagnosed in 

either screening or non-screening cohorts published in the 21st 

century have cirrhosis [47]. In a multi-institutional study, cirrhosis in 

patients with p.C282Y/p.C282Y was significantly associated with age, 

diabetes, daily alcohol intake, and iron removed by phlebotomy, taking 

into account the effect of other variables, although the prevalence of 

fatty liver/steatosis did not differ significantly in 86 adults with and 282 

adults without cirrhosis (27.4% and 33.0%, respectively; p = 0.4400) 

[8]. In a large study of healthcare records in UK, Netherlands, Italy and 

Spain, the hazard ratio for cirrhosis in patients with NAFLD was 4.73 

(95% CI [2.43, 9.19]), although the strongest independent predictor of 

cirrhosis was a baseline diagnosis of diabetes [48]. In a study that did 

not include subjects with p.C282Y/p.C282Y, SF, age, BMI, and diabetes 

were independent predictors of histologic severity and advanced 

fibrosis in patients with NAFLD [49]. Together, these observations 

suggest that age and diabetes are greater risk factors for cirrhosis in 

adults with p.C282Y/p.C282Y than NAFLD. 

In summary, the percentage of the present hemochromatosis 

probands with NAFLD (24.2%; 95% CI [14.9, 36.6]) was higher than 

that of whites in general U.S. populations (14.4%; 95% CI [14.0, 14.8]) 

[3]. In a metaanalysis of global populations, co-morbid conditions 

associated with NAFLD included obesity, T2DM, hyperlipidemia, 

hypertension, and MetS [2], whereas T2D alone was significantly 

associated with NAFLD in the present hemochromatosis probands. 

Referring physicians diagnosed and treated the present probands with 

diabetes, hypertension, and hyperlipidemia and thus their evaluations 

and diagnostic criteria for these disorders may differ from those of 

large population studies. LDL cholesterol [39, 45] and total cholesterol 

[45] levels are lower in adults with HFE p.C282Y/p.C282Y than wt/ 

wt. These factors could account in part for the absence of NAFLD 

risk factors we studied in 18.8% of the present probands. It is also 

plausible that probands without NAFLD risk factors we studied have 

other undiagnosed or undocumented conditions that increase NAFLD 

risk, including obstructive sleep apnea [50], hypothyroidism [51, 52], 

hypopituitarism [53], or heritable disorder(s) [15, 16]. 

A strength of the present study is analyses based on observations 

of non-screening adults with hemochromatosis, iron overload, and 

HFE p.C282Y/p.C282Y, with or without NAFLD, who did not report 

alcohol consumption > 14 g/d, have cirrhosis or other liver disorders, 

report using steatogenic medication, or have diagnoses of heritable 

disorders that increase NAFLD risk. The present study does not 

permit a comparison of the sensitivity and specificity of liver biopsy, 

ultrasonography, and CT scanning in diagnosing NAFLD. It is also 

plausible that the lack of significant difference of the prevalence of 

NAFLD co-morbid factors other than T2DM we studied between 

probands with and without NAFLD may in part reflect type 2 statistical 

error(s). Evaluating subgroups of probands with NAFLD based on ALT/ 

AST values or liver morphology [2] or alcoholic/non-alcoholic fatty liver 

scores/indices, detecting alleles associated with increased NAFLD 

risk [15, 16], determining the effects of therapeutic phlebotomy on 

ALT and AST levels, treating NAFLD, and evaluating of post-diagnosis 

observations other than QFe were beyond the scope of this work. 

Conclusions 

We conclude that NAFLD in hemochromatosis probands with iron 

overload and HFE p.C282Y/p.C282Y is associated with higher median 

SF and greater T2DM prevalence, after adjustment for other factors. 

NAFLD does not influence QFe significantly. 

List of abbreviations 

ALD alcoholic liver disease 

ALT alanine aminotransferase 

ANI alcoholic liver disease/non-alcoholic fatty liver disease index 

APRI AST-to-platelet ratio index 

AST aspartate aminotransferase 

BMI body mass index 

CI confidence interval 

FIB-4 fibrosis-four variables 

HFE homeostatic iron regulator gene 

HLA human leukocyte antigen 

LDL low-density lipoprotein 

MetS metabolic syndrome 

NAFLD non-alcoholic fatty liver disease 

QFe quantity of iron removed by phlebotomy to achieve iron depletion 

SD standard deviation 

SE standard error 

SF serum ferritin 

T2DM type 2 diabetes mellitus 

TS transferrin saturation 

Supplementary Information 

The online version contains supplementary material available at 

https://doi.org/10.1186/s12876-023-02763-x. 

Supplementary Material 1. Definitions of other conditions 

Acknowledgements 


Author contributions 

JaCB evaluated probands, conceived this study and its methodology, 

curated data, performed analyses, and drafted the manuscript. JClB 

conceived study methodology, curated data, performed analyses, and 

drafted the manuscript. RTA conceived this study and its methodology, 

performed analyses, and drafted the manuscript. Each author 

approved the manuscript in its final form. 

Funding 

The authors received no specific funding for this work. 


22 23

FEATURE 

FEATURE 


Data Availability 

The dataset generated and/or analysed during the current study is 

available in the Open Science Framework repository (https://osf.io/ 

j5gsp/). Data were compiled and displayed in a manner that maintains 

proband anonymity. Definitions of hemochromatosis arthropathy, 

hypogonadotropic hypogonadism, cirrhosis, and cardiomyopathy are 

displayed in Additional file 1 [.docx; Other diagnostic criteria]. 

Declarations 

Ethics approval and consent to participate 

This work was performed according to the principles of the Declaration 

of Helsinki [43]. Performance of this study was approved by Western 

Institutional Review Board, Inc. (submission 2539985–44189619). 

The need for obtaining informed consent from participants in this 

study was waived by Western Institutional Review Board under United 

States Department of Health and Human Services, Office for Human 

Research Participants, regulation 45 CFR 46.101(b)(4). 

Consent for publication 


Competing interests 

None of the authors has a conflict of interest to report. 

Received: 13 January 2023 / Accepted: 11 April 2023 

Published online: 28 April 2023 

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of histologic severity and advanced fibrosis in patients with 

jurisdictional nonalcoholic claims fatty in published liver disease. maps Hepatology. and institutional 2012;55:77–85. affi liations. 

50. Mesarwi OA, Loomba R, Malhotra A. Obstructive sleep apnea, 

Open hypoxia, Access and This nonalcoholic article is licensed fatty under liver disease. a Creative Am Commons J Respir Crit Care 

Med. 2019;199:830–41. 

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51. Lonardo A, Ballestri S, Mantovani A, Nascimbeni F, Lugari S, Targher 

adaptation, G. Pathogenesis distribution of and hypothyroidism-induced reproduction in any medium NAFLD: or evidence format, as for a 

long as distinct you give disease appropriate entity? credit Dig Liver to the Dis. original 2019;51:462–70. author(s) and the source, 

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