Introduction

Hepatocellular Carcinoma (HCC) is a major type of primary liver cancer and one of the most frequent human malignant neoplasm. Owing to the lack of reliable clinical HCC markers, fewer than 20% of patients are diagnosed at a stage where curative treatment can be performed. Aldo-keto reductase family 1 member Bl0 (Akr 1 Bl0), cancer-related oxireductase was originally identified as a gene whose expression was upregulated in human HCC but was low in normal liver tissue. Akr l Bl0 upregulation was observed in several studies in certain chronic liver diseases such as chronic hepatitis B and C and steatohepatitis, which are widely recognized to represent a precancerous condition of HCC.

Aims & Methods

The aim is to investigate the role of serum AKR1B10 as a screening test for early detection of HCC in HCV related liver cirrhosis.
Methods: The study was carried out on 60 Egyptian patients with HCV related liver cirrhosis (Liver cirrhosis (LC) group: 30 patients with HCV related liver cirrhosis without HCC and HCC group: 30 patients with HCV related liver cirrhosis and HCC) and 20 healthy volunteers as controls from Menoufia University Hospitals (Egypt). They underwent history taking, physical examination and laboratory investigations (CBC, liver profile {ALT, AST, albumin, bilirubin, INR}, urea, creatinine, AFP, HBsAg, HCV Ab and serum AKR1B10). Abdominal ultrasonography was done for all patients and controls. HCC is further confirmed by triphasic CT. Patients with malignancy other than HCC, advanced HCC, received previous treatment for HCC, age <18 years old, HCC with distant metastasis and chronic liver disease other than HCV were excluded from the study.

Results

In HCC group, All patients had single lesion, 40% (n=12) in left lobe and 60% (n=18) in right lobe. HCC size was 5.7±2.5 cm (range 4.3 to 8.2 cm). No portal vein thrombosis was detected. In HCC group, according to BCLC classification, 22 patients (73.3%) were in A2 stage and 8 (26.7%) in A3 stage. According to TNM classification, all patients were in stage T1bN0M0. Serum AKR1B10 (pg/ml) was significantly higher in HCC group (3837.7±334.7) than LC (1176±187.7) and control group (664.7±402.2) (P˂0.001 for all). Also serum AKR1B10 (pg/ml) was significantly higher in LC group than in control group (P˂0.001). AFP level (ng/ml) was significantly higher in HCC group (6173±14080) than LC (12.7±5.6) and control group (7.2±4.3) (P˂0.001 for both). Also AFP level (ng/ml) was significantly higher in LC group than control group (P˂0.001). Serum AKR1B10 (pg/ml) at cutoff level >0.95 have 86.7% sensitivity and 70% specificity for detection of HCC. AFP at cutoff level >17.9 ng/ml have 67% sensitivity and 88% specificity for detection of HCC. Combined Serum AKR1B10 and AFP have 97.6% sensitivity and 100% specificity for detection of HCC. There was no significant difference between HCC and LC group as regard MELD score (19.6±0.5 and 19.5±0.5 respectively), APRI score (1.48±0.68 and 1.67±0.94 respectively), FIB-4 (2.05±1.79 and 2.35±2.26 respectively) and Child-Pugh score (6.3±1.5 and 5.9±0.3 respectively) (P˃0.05). In LC group, 27 patients (90%) were in Child class A, 3 patients (10%) were in Child class B. In HCC group, 24 patients (80%) were Child A, 6 patients (20%) were Child B.

Conclusion

AKR1B10 could be used as a diagnostic biomarker for early detection of HCC in HCV‑related cirrhosis, as it showed significant upregulation in patients with HCC in comparison with non‑HCC patients.

References

- Han C, Gao L, Bai H, Dou X. Identification of a role for serum aldo‑keto reductase family 1 member B10 in early detection of hepatocellular carcinoma. Oncol Lett. 2018;16(6):7123-30
-Murata, A, Genda, T, Ichida, T, Amano, N, Sato, S, et al. Pretreatment AKR1B10 expression predicts the risk of hepatocellular carcinoma development after hepatitis C virus eradication. World J Gastroenterol. 2016;22(33):7569-78
- Mori M, Genda T, Ichida T, Murata A, Kamei M, Tsuzura H, et al. Aldo‐keto reductase family 1 member B10 is associated with hepatitis B virus‐related hepatocellular carcinoma risk. Hepatol Res. 2017;47(3):E85-93
-Jin J, Liao W, Yao W, Zhu R, Li Y, He S. Aldo-keto reductase family 1 member B 10 mediates liver cancer cell proliferation through sphingosine-1-phosphate. Sci Rep. 2016;6:22746
-Ye X, Li C, Zu X, Lin M, Liu Q, Liu J, et al. a large-scale multicenter study validates aldo-keto reductase family 1 member B10 as a prevalent serum marker for detection of hepatocellular carcinoma. Hepatology. 2019;69(6):2489-501
- Kanno M, Kawaguchi K, Honda M, Horii R, Takatori H, Shimakami T, et al. Serum aldo-keto reductase family 1 member B10 predicts advanced liver fibrosis and fatal complications of nonalcoholic steatohepatitis. J Gastroenterol. 2019;54(6):549- 57

Clinical Case Summary

A 78-year-old female with personal history of ischemic cardiomyopathy and atrial fibrillation was referred to a tertiary center due to iron deficiency anemia without clinical evidence of gastrointestinal bleeding. The patient required periodic erythrocyte transfusion and intravenous iron treatment. An upper and lower endoscopy was performed, yielding unremarkable findings.
In this context, the patient underwent capsule endoscopy which revealed an ileal polypoid ulcerated lesion close to a Meckel diverticulum. Subsequently, a double balloon retrograde enteroscopy was performed, with identification of a Meckel diverticulum without ulcers nor active bleeding. Furthermore, a 15-millimeter diameter polypoid lesion was also seen and removed using a diathermic snare after submucosa injection, clip and loop application. The histopathological report confirmed a pyogenic granuloma, also known as lobular capillary hemangioma. After lesion removal the patient experienced anemia resolution.
Pyogenic granuloma is a rare benign proliferation of capillary vessels, most commonly affecting the skin and oral mucosa, characterized by friable bright red papules. Nevertheless, gastrointestinal involvement can also occur. The high vascularization associated with these lesions justifies the presence of iron deficiency anemia due to gastrointestinal losses. This case highlights a rare small bowel pyogenic granuloma. Despite its association with iron deficiency anemia, the occurrence of a pyogenic granuloma in this context, particularly in the enteric mucosa, is uncommon. Nevertheless, recent studies suggest that this clinical entity may be underdiagnosed due to improper identification of inflammatory or hyperplastic polyps. Capsule endoscopy and device assisted enteroscopy were crucial in localizing and ensuring proper therapeutic management of this lesion, thereby solving the iron deficiency anemia.

References

1. Capsule endoscopy images with identification of the Meckel diverticulum and pyogenic granuloma
2. Device-assisted enteroscopy images with identification of the Meckel diverticulum and pyogenic granuloma
3. Histopathological sample of pyogenic granuloma

Introduction

The direct link between nutritional status and lung function, and survival in cystic fibrosis (CF) is unambiguous, so diet therapy for this disease is an important part of the treatment.

Aims & Methods

To study the influence of colostrum supplements in CF based on the evaluation of symptoms and values of antimicrobial peptides and proinflammatory cytokines.
A total of 56 children aged from 2 months to 3 years with cystic fibrosis were included. To make a diagnosis of CF we used determination of immunoreactive trypsin, sweat chlorides and genetic studies. Fecal calprotectin, fecal β-defensin 2 levels, as well as Il-1β values and antibody concentrations to cell permeability-increasing protein in serum were determined in patients. Colostrum was included in addition to basic therapy. The exclusion criteria were children with allergies to cow's milk protein, which made up 16 children. Colostrum was administered to 22 children according to the age dosages: up to 1 year -0.25 ml * 3 times a day, from 1 to 3 years - 0.5 ml * 3 times, 3-12 years - 1 ml * 3 times. The duration of use was 3 months. The control group consisted of 18 children on basic therapy.

Results

The cough with a discharge of viscous sputum which was observed in 36 children (90.0%) on admission to the hospital, remained in every fourth child after the basic therapy - 5 (27,7%, p<0.002). We registered a sixfold reduction of the number of patients with cough and viscous sputum - 3(13,6%, р<0.001) with modified therapy.
On the basic therapy protein-energy deficiency of a severe degree (-3SD) persisted in every fifth child - 4 (22,2%), moderate degree of protein-energy deficiency - in half of all patients - 9 (50%). On the modified therapy, the number of patients with protein-energy deficiency increased due to -2CO (27.7%) and -1CO (59.1%), while none of the patients had severe protein-energy deficiency.
After basic therapy, fatty stool was detected in 5 (27,8%, p<0.001), then in children of the second group this index reliably decreased by 7.3 times compared to the condition before admission (13.6%, p<0.001). In the first group children with polyfecalia recorded in 3 (16.7%, p<0.02 vs. admission), while in the second group the figure was 3.7 times less frequent (p<0.002).
The proinflammatory cytokine Il-1β had a fivefold excess at admission compared with control values. In the dynamics on the modified therapy the value of this index came to normal - 2,9+0,8 pg/ml, twofold excess was kept in the first group.
The level of antimicrobial peptides (fecal calprotectin and β-defensin) was significantly increased in comparison with reference values at admission. Fecal calprotectin decreased after 3 months on the basic therapy and was more pronounced in the group with modified therapy - 52,2±2,8 mcg/g, p<0,002, but they did not reach reference values, remaining three times higher than normal (p<0,001). A similar picture was observed in the estimation of β-defensin level. The most pronounced decrease (1,5 times) was observed in patients on the modified therapy - 72,1 ±3,6 ng/ml, p<0,001. Values in this group practically approached to the norm, which could not be said about the group with basic therapy (93,4±5,4 ng/ml, p<0,001).

Conclusion

The use of colostrum supplementation in the complex treatment of cystic fibrosis with basic therapy has a positive effect on the clinical course and reduces the activity of antimicrobial peptides and proinflammatory cytokines in children with cystic fibrosis.

Introduction

Difficult liver pathology cases often require expert review for optimal patient care. We reviewed consult cases received in our reference centre aiming to highlight challenging areas in hepatopathology that may benefit from consultation and focused educational activities.

Aims & Methods

We included all medical liver biopsies received for primary consultation in our Department between October 2016 and December 2022. Data on the sender (clinician/pathologist/patient) and the reason for consultation were collected. Initial and consult reports were screened for adequacy of clinical/laboratory/imaging information received, stains performed, initial and final diagnosis, disease grading/staging and comment on aetiology with suggestions to the clinician, where appropriate. Statistical analysis was performed using one sample t tests and descriptive statistics.

Results

We retrieved 147 consult cases (84 female-57.1%, median age 51, range 13-86 years), 135 (92.5%) submitted by hepatologists, 10 (6.9%) by pathologists and 1 (0.6%) by a patient. Adequate clinical/biochemical/imaging information was available in only 35/131 (26.7%) initial reports, while 51 (38.9%) did not have any information. Additional data was available with the consult in 122/147 (83%) cases but in 38 (25.8%) this was acquired by the consultant pathologist. Additional histochemical stains and immunostains were performed in 111 (78.7%) consult cases, while unnecessary stains had been initially performed in 30 (23.1%) cases. Most common reasons for consultation were confirmation of initial diagnosis 74 (50.3%), autoimmune hepatitis-AIH? 17 (11.6%), nonalcoholic steatohepatitis-NASH? 11 (7.5%) and primary biliary cholangitis-PBC? 11 (7.5%). Most common initial diagnoses were non-specific changes, chronic hepatitis, NASH and drug induced liver injury-DILI while most common consult diagnoses were vascular diseases, PBC, AIH, NASH and DILI (p<0.001, more details in Τable 1). Major changes in the initial diagnosis occurred in 73 (54.9%), minor changes in 37 (27.8%) and no change in 23 (17.3%) consults. Absence of adequate liver special stains, disease aetiology, grading/staging and comments/suggestions was recorded in 100 (76.9%), 71 (55.5%), 51 (45.1%) and 65 (49.6%) of initial reports, respectively (p<0.001compared to consults).

Table 1.
Diagnosis	Initial Report n (%)	Consult Report n (%)
Non specific changes	37 (27.8%)	7 (4.8%)
Chronic hepatitis	17 (12.8%)	1 (0.7%)
NASH	10 (7.5%)	14 (9.6%)
DILI	8 (6%)	12 (8.2%)
AIH	8 (6%)	17 (11.6%)
PBC	6 (4.5%)	19 (13%)
Vascular diseases	3 (2.3%)	22 (15.1%)

Conclusion

Study of consult medical liver biopsy patterns provides useful information on areas of hepatopathology posing diagnostic difficulty. The majority of consult cases in our Department are submitted by hepatologists. The most common diagnostic challenges in medical liver biopsies are vascular liver disease, interpretation of hepatitic pattern of injury, and recognition of primary cholangiopathy. These areas can be the subject of future continuing medical educational activities in hepatopathology.

Introduction

With a prevalence of 1-2%, celiac disease (CD) is one of childhood’s most common chronic diseases. Clinical follow-up of CD aims to ensure adherence to a strict gluten-free diet, monitor symptoms and prevent disease-related complications. However, few studies have examined health outcomes of children who lack CD follow-up. Related to this knowledge gap, there have until recently been no evidence-based pediatric guidelines on CD follow-up.

Aims & Methods

To examine the association between the lack of follow-up for celiac disease (CD) during childhood and dietary adherence, disease remission status, and health-related quality of life (HRQoL).
In a cohort of 162 children diagnosed with CD in 2013-2018 in Gothenburg, Sweden we retrieved information on clinical follow-up and current wellbeing using data from medical and laboratory records, as well as validated questionnaires on symptoms of CD, dietary adherence, and HRQoL. We analyzed tissue-transglutaminase antibodies (tTGA) as a measure of disease remission. We defined lack of follow-up as no CD-related physician/dietician-led visit or measurement of tTGA over the past 24 months of study enrollment.

Results

The mean age at study assessment was 12.7 (range 7.8-18.2) years. Out of 162 children with an average disease duration of 5.3 (range 2.3-8.8) years, 23 (14%) lacked follow-up. The tTGA had normalized (<7/ml) in 94% (95% confidence interval [CI]=71-100) of children without follow-up versus 91% (95% CI=85-95%) of children with continued follow-up. Of children without follow-up, 65% (95% CI=38-86%) reported a dietary adherence score indicating very good adherence, versus 72% (95% CI=63-80%) of those with continued follow-up. Mean dietary adherence scores were similar between groups (p=0.93). Also, lack of follow-up was not significantly associated with growth, symptom scores, or HRQoL.

Variable n(%)	Total (n=162)	Continued follow-up (n=139)	Lack of follow-up (n=23)	p-value
Age, years at study enrollment Mean (SD), range	12.7 (2.8) 7.8-18.2	12.7 (2.6) 8.0-18.2	13.2 (3.6) 7.8-18.2	0.68
Years since CD diagnosis Mean (SD), range	5.3 (1.7) 2.3-8.8	5.2 (1.8) 2.3-8.8	5.8 (1.6) 3.1-8.1	0.11
Sex (Girls)	94 (58%)	85 (61%)	9 (39%)	0.08
Biopsy-verified CD diagnosis	65/162 (40%)	60/139 (43%)	5/23 (22%)	0.08
Dietary adherence (CDAT) score, mean (SD)		11 (3.4)	11 (3.4)	0.93
Gastrointestinal Rating Scale (GSRS)Total score, mean (SD)		1.7 (0.7)	1.5 (0.6)	0.13
KIDSCREEN-27 Raw score; median (min; max)		110 (69; 134)	115 (87; 134)	0.55
CDDUX total score, mean (SD)		2.4 (0.8)	2.4 (0.86)	0.91
tTGA* negative <7 U/mL n(%; 95% CI)		91 (91%; 84-96%)	16 (94%; 71-100%)	0.58**

Teble legend: Lack of follow-up was defined as no registered visit for CD or tTGA over the past 24 months of study enrollment. *Including ten children with a tTGA measurement recorded within 30 days of study enrolment. **Refers to the distribution of negative <7, positive 7-100 and positive >100 U/ml between the two groups.
The Swedish version of CDAT was used to assess gluten-free dietary adherence.^{1, 2} A score of <13 has been considered indicative of a very good adherence (corresponding to standardized dietician evaluation: consumes gluten <3 times/year, reads labels well, cross-contamination potential eliminated in the kitchen).² Scores >17 are indicative of poor adherence (corresponding to standardized dietician evaluation: gluten consumption 1-2/week, does not check medications/supplements, cheats regularly and intentionally [1x/week]).² Scores of 13-17 are inconclusive.²
KIDSCREEN-27 sub-scores have been transformed into T-scores. A mean of 50 (standard deviation, SD) +/-10 defines normality for European children aged 8-18 years. A higher score indicates a better HRQoL. A between-group-difference of 0.5 SD or a difference of 0.5 SD from European/National norms, is considered noticeable. ³
CDDUX ranges from 1 to 5. Higher scores indicate better CD-related HRQoL.⁴

Conclusion

In this regional cohort study of mostly oder children and adolescents, lack of follow-up for CD was not significantly linked to dietary adherence, disease remission status, or HRQoL. How these results hold in larger samples with longer follow-ups, including the transition to adult care, warrants further study.

References

^​1. Johansson K, Norström F, Nordyke K, et al. Celiac Dietary Adherence Test simplifies Determining Adherence to a Gluten-free Diet in Swedish Adolescents. J Pediatr Gastroenterol Nutr 2019;69:575-580.
2. Leffler DA, Dennis M, Edwards George JB, et al. A simple validated gluten-free diet adherence survey for adults with celiac disease. Clin Gastroenterol Hepatol 2009;7:530-6, 536.e1-2.
3. Ravens-Sieberer U, Europe KG. The Kidscreen questionnaires: quality of life questionnaires for children and adolescents; handbook: Pabst Science Publ., 2006.
4. van Doorn RK, Winkler LM, Zwinderman KH, et al. CDDUX: a disease-specific health-related quality-of-life questionnaire for children with celiac disease. J Pediatr Gastroenterol Nutr 2008;47:147-52.