Clinical Case Summary

Introduction: Congenital hepatic fibrosis (CHF) is a rare autosomal recessive disorder characterized by pathological ductal plate malformation; ciliopathy or fibrocystic liver disease¹. It often presents with hepatosplenomegaly, portal hypertension, and renal abnormalities.²
Case study: A 32-years-old female presented to our clinic by hematemsis. Regarding medical history, she did not report any symptoms related to her liver. She has a non-relevant family history. Physical examination showed pallor, splenomegaly, attained puberty with normal secondary sexual characters. On evaluation, Hb was 9.4 g/dl, Platelets 88*10^3/ ul, WBCs 3.7*10^3/ ul, Alt was 49 u/l, AST 63u/l, S. albumin 3.8 g/dl, total bilirubin 1.20 mg/dl, direct bilirubin 0.3 mg/dl, S.ferritin 47.6 ng/ml, TIBC 257 ug/dl, HCV Ab and HBsAg were negative, AIH panel was negative. Abdominal ultrasound revealed established cirrhotic changes of liver, mild non calcular cholecystitis, normal caliber CBD with echo-free lumen and splenomegaly 18 cm in bipolar dimensions as well as polycystic kidney disease with no evidence of ascitis.
Upper G.I endoscopy showed one cord of Grade II esophageal varices with risky signs and mild portal hypertensive gastropathy, EBL was done.
MRCP revealed ectatic intrahepatic biliary radicales with no significant dilatation of CBD (5mm) and no signal void stones are seen in CBD or gall bladder, diffuse hepatic cirrhosis and splenomegaly and bilateral polycystic kidneys were noticed.
Liver needle core biopsy and pathological examination were done, Hepatic parenchyma is divided into islands separated by wide thick fibrotic septae which showed numerous proliferating bile ductules, hypoplastic branches of the portal vein and inspissated bile in bile ductules , picture highly suggestive of CHF.
Conclusion: This case highlights the importance of considering CHF as a differential diagnosis in patients presenting with hepatosplenomegaly, portal hypertension, and dilated intrahepatic bile ducts.

References

1. Zhu B, Du Z, Wang Z, Li Y, Zhang J, Zhu H. Congenital Hepatic Fibrosis in Children and Adults: Clinical Manifestations, Management, and Outcome-Case Series and Literature Review. Gastroenterol Res Pract. 2020 Apr 21;2020:8284274. doi: 10.1155/2020/8284274. PMID: 32382272; PMCID: PMC7191434.
2. Mankala VM, Davis JL, Patel CV, Lin HC. Congenital Hepatic Fibrosis Presenting With Pancytopenia. JPGN Rep. 2021 Jan 13;2(1):e043. doi: 10.1097/PG9.0000000000000043. PMID: 37206942; PMCID: PMC10191487.

Introduction

Congenital hepatic fibrosis (CHF) is a rare autosomal recessive disease derived from biliary dysgenesis secondary to ductal plate malformation; it often coexists with Caroli’s disease, von Meyenburg complexes, autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). Congenital hepatic fibrosis (CHF) and Caroli syndrome has varied clinical presentations with or without renal involvement.

Aims & Methods

Our study aimed to describe the clinical manifestations and natural history of children with CHF and Caroli with or without renal involvement. Retrospective data from January 2022 to January 2024 was collected and analyzed.

Results

Twenty-three children (Caroli=7, CHF=16) were enrolled male predominance (76%) was noted. Consanguinity was noted in 76% and 23% had affected siblings. Median age at initial presentation was two years and abdominal distension was the most common presentation (47.6%) followed by variceal bleeding (23.8%), cholangitis (14.2%), incidental diagnosis (9.5%) and pancytopenia (4.76%). Median age at presentation and diagnosis was later with variceal bleeding at 5.6 years compared with children with abdominal distension who presented at 18 months respectively (p=0.0001). Renal involvement was present in 76% of the children. Autosomal Recessive Polycystic Kidney Disease (ARPKD) was the most common renal manifestation noted. Of them, 18% had developed Chronic Kidney Disease (CKD). All Caroli cases (100%) had renal involvement. There was no statistical difference in the age of presentation of CHF with or without renal involvement (p=0.5998). Growth faltering was noted in 52% of children. Statistical analysis revealed no significant difference in the likelihood of developing portal hypertension among children with either congenital hepatic fibrosis (CHF) or Caroli disease, regardless of renal involvement. Portal hypertension was seen in 76%. Only one child had variceal bleeding on follow up.

Conclusion

Abdominal distension, organomegaly, variceal bleeding, and cholangitis are frequently observed clinical manifestations in both congenital hepatic fibrosis (CHF) and Caroli disease. Interestingly, while renal involvement is more prevalent in Caroli disease compared to CHF, there doesn't appear to be a direct correlation between renal involvement and the severity of hepatic manifestations or growth faltering in affected children. This underscores the complexity of these conditions and the need for tailored management approaches that address both hepatic and renal complications.

References

1. Srinath, Arvind, and Benjamin L Shneider. “Congenital hepatic fibrosis and autosomal recessive polycystic kidney disease.” Journal of pediatric gastroenterology and nutrition vol. 54,5 (2012): 580-7. doi:10.1097/MPG.0b013e31824711b7
2. Gunay-Aygun M, Font-Montgomery E, Lukose L, Tuchman Gerstein M, Piwnica-Worms K, Choyke P, Daryanani KT, Turkbey B, Fischer R, Bernardini I, Sincan M, Zhao X, Sandler NG, Roque A, Douek DC, Graf J, Huizing M, Bryant JC, Mohan P, Gahl WA, Heller T. Characteristics of congenital hepatic fibrosis in a large cohort of patients with autosomal recessive polycystic kidney disease. Gastroenterology. 2013 Jan;144(1):112-121.e2. doi: 10.1053/j.gastro.2012.09.056. Epub 2012 Oct 3. PMID: 23041322; PMCID: PMC4162098.

Introduction

The coexistence of HBV and hepatic steatosis is frequent, but its impact on the progression of liver disease remains poorly characterized and much debated.

Aims & Methods

We aim by this study to determine the prevalence, associated factors, consequences of this association and response to treatment.
A retrospective analysis was conducted over 20 years from 2005 to 2025 on a single-center cohort of 124 patients with chronic HBV, of whom 16.1% (n=20) had steatosis (confirmed by imaging). Demographic, virological, metabolic and histological (fibrosis stage) characteristics were compared between the groups with and without steatosis. And statistical tests (Chi², Mann-Whitney, logistic regression) were used.
For the comparison, we defined:
- Group A: combining steatosis and HBV
- Group B: HBV without steatosis.

Results

The prevalence of steatosis in patients with HBV in our series was 16.1%, with a mean age of 52.1 years higher than that of patients with HBV without steatosis, (45.8 years), with a p-value of 0.02. Furthermore, in our work there was a clear female predominance, with a sex ratio of 3 F/H in group A vs 0.9F/H in group B with a p-value of 0.04.
In the history of our patients, we found that 30% of patients had high blood pressure in group A compared with 18% in group B, 10% had diabetes in group A compared with 8% in the other group, and there was no significant difference in smoking habits (15% compared with 12%). Statistical regression did not find any significant correlation in those signs. On the other hand, in the case of dyslipidemia, there was a slight predominance of group A (15% vs. 10%) with a p-value of 0.045.
The analysis of hepatic test didn’t show any big difference between results of GGT, PAL and ASAT but for ALAT there was a higher in patients with steatosis with a median of 62 vs 52,1 and a p-value of 0,02.
Our study also found no difference in serological results: 95% of patients with steatosis were Hbs Ag positive, with the presence of Hbc Ab in all patients at the time of diagnosis. These results were not very different from those of patients without steatosis (Hbs Ag positive in 96.8% and Hbc Ab positive in all patients). Only 10% of patients had a positive Hbe Ag in group A vs 7.2% in group B. The median viral load before treatment was 1870 UI/ml vs 2450 UI/ml with no real difference noted between the 2 groups, confirmed by statistical regression which found a p=0.82 value.
Our study found no real impact on liver disease, showing no worsening of fibrosis (30% F≥2 with steatosis vs 25% without, p=0.62*).
After analysis using the association Chi² test, our study found similar virological responses under treatment (83% in group A vs 78% in group B, p=0.75*).

Conclusion

In this cohort, steatosis in HBV patients (16.1%) was associated with age and female sex. Hepatic test showed a higher ALAT fold among patient with steatosis. However, higher viral load or more severe fibrosis was not demonstrated. Steatosis in HBV does not appear to have a negative influence on the course of the disease. These results suggest that the management of HBV with steatosis should primarily target virological control, without requiring any specific therapeutic adaptation.

Disclosure

no conflict of interest

Introduction

To the best of our knowledge, there is no study addressed the HCC recurrence rates after radiofrequency ablation (RFA) in those achieved long-term sustained virologic response (SVR) before HCC development versus SVR for less than 2 years or no SVR before HCC occurrence.

Aims & Methods

The study aimed to identify the predictors of early HCC recurrence after RFA and explore the relationship with SVR duration among patients with HCV-related liver cirrhosis.
This study is a retrospective one that included patients with HCV-related liver cirrhosis and HCC who had RFA. Those with positive HBsAg, alcohol-associated liver disease, patients with other known causes of chronic liver disease, and patients with locoregional therapy other than RFA were excluded. A fine needle aspiration biopsy was done at the time of the RFA. A 2-year retrospective follow-up was done. Those with missing data, lost follow-up, or died before any HCC recurrence were excluded. A total of 64 patients were included in the study.

Results

During the 2-year follow-up starting from the date of RFA procedure, 26 patients (40.6%) experienced HCC recurrence. There were no statistically significant differences between those who experienced HCC recurrence and those who did not regarding age, sex, baseline hemoglobin levels, platelets, white blood cell counts, ALT, AST, INR, albumin, total bilirubin, FIB-4, MELD, ALBI, and Child-Pugh scores. Also, there were no statistically significant differences between the two groups regarding the number of lesions. On the other hand, the mean size of the largest lesions was significantly larger in the HCC recurrence group. The mean was 4.3±0.78 cm in the HCC recurrence group, while it was 3.38±1.05 cm in the non-recurrence group (p<0.001). Also, the baseline AFP was significantly higher in the HCC recurrence group. The median was 225 (IQR 90–894) ng/ml, against 11.3 (IQR 7.5–70) ng/ml in the non-recurrence group (p<0.001).
Those who received DAAs 2 years before HCC occurrence showed the least incidence of HCC recurrence (p = 0.001). Regarding the pathological grade, 65.4% of the HCC recurrence group had grade III HCC, 34.6% had grade II, and no one of them had grade I HCC on histopathological examination. The difference was statistically significant (p=0.012).
On multivariate regression analysis, it was found that AFP significantly increased the odds of HCC recurrence (OR = 1.004, 95% CI 1.001–1.007, p = 0.016). Also, the increase in size of the largest lesion significantly increased the risk of HCC recurrence (OR = 3.039, 95% CI = 1.514–6.1, p = 0.025). Receiving successful DAA therapy 2 years before the occurrence of HCC significantly decreased the odds of HCC recurrence (OR = 0.016, 95% CI 0.028–0.413, p = 0.016). On the other hand, the histopathological grade of HCC failed to show a significant change in the odds of HCC recurrence.

Conclusion

In conclusion, larger tumor size and higher pre-ablation AFP levels predicts HCC recurrence after RFA, while long-term SVR for more than 2 years before HCC occurrence predicts lower rates of HCC recurrence after RFA.

Introduction

The treatments for liver fibrosis are still in need so far. As the crucial initiators, activated hepatic stellate cells (aHSCs) undergo a series of epigenetic changes. The study intends to explore transcription factors (TFs) that facilitate HSCs activation and provide novel therapeutic targets for liver fibrosis.

Aims & Methods

Three distinct HSCs activation models were established in present study. Firstly, in vitro activation involved isolating primary HSCs from normal Sprague-Dawley rats and culturing them for two days (n=5) and seven days (n=5), namely natural activation model. Secondly, in vivo activation entailed isolating primary HSCs from bile duct ligated rats (n=4) and normal controls (n=4), followed by culturing until the next day. Lastly, transforming growth factor-β (TGF-β, 2.5ng/ml) (n=10) or control buffer (n=10) were added to the human HSCs cell line LX2 and cultured for 24 hours. Subsequently, assay for transposase-accessible chromatin using sequencing (ATAC-seq) was conducted on the abovementioned cells, along with motif enrichment and footprint analysis. Pathway enrichment analysis was performed on differentially accessible genes (DAGs). RNA sequencing (RNA-seq) was employed to analyze gene expression profiles of primary HSCs in the natural activation model (n=4). The integration of ATAC-seq and RNA-seq further identified potential key TFs. RT-qPCR and differential expression analysis of public datasets was utilized to confirm the dysregulation of TFs in primary HSCs, fibrotic liver and fibrotic model of induced pluripotent stem cells. Finally, enrichment at enhancers and promoters of these genes was validated by H3K27Ac and H3K4me3 chromatin immunoprecipitation followed by sequencing (ChIP-seq) of human HSCs.

Results

For ATAC-seq, primary HSCs exhibited higher chromatin accessibility after activation compared with the controls. After peak annotation, the up-regulated peaks were mainly located in the promoter region in all comparison groups, uncovering the dynamic transcriptional regulation during HSC activation. In the motif enrichment analysis, 150 aHSCs related TFs and 54 quiescent HSCs (qHSCs) related TFs were identified in the in vitro activation model. The three models shared 12 aHSCs related TFs, namely Runx-aml, Runx1, Runx2, Runx, Ets:Runx, Atf2, Atf4, Atf7, c-Jun-Cre, Creb5, Smad3 and CArG; and 19 qHSCs related TFs, including Foxf1, Foxo3, Foxk1, Foxp1, Hoxa1, Hoxa2, Stat3, Hnf4a, Hnf6, Elk1, Elk4, Cux1, Crx, Duxbl, Vdr, Tr4, Ebf2, Gata2, Gata6. Footprint analysis validated the alteration of accessibility in Atf2, Atf4, Atf7, Creb5, Hnf6 and Gata2. Actin filament organization, Ras protein signal transduction and intrinsic apoptotic signal pathways were enriched in DAGs. Integration of ATAC-seq and RNA-seq showed that gene expression was significantly correlated with chromatin accessibility, among which Runx2, Creb5, and Smad3 were significantly upregulated in aHSCs at transcription level. The dysregulation of these three genes was verified in primary HSCs, fibrotic liver and fibrotic model of human induced pluripotent stem cells. Finally, enrichment at active enhancers and promoters of these TFs was validated by H3K27Ac and H3K4me3 ChIP-seq of human HSCs, revealing the crucial role of genes in the transcription.

Conclusion

We generated chromatin accessibility profiles of different HSCs activation models, highlighting the significance of Runx2, Creb5, and Smad3 as key TFs mediating HSCs activation. These findings proposed these TFs as promising targets for future liver fibrosis treatment.

Disclosure

The author declare no competing interests and financial relationships with commercial interests.

Clinical Case Summary

We report a rare and fatal case of diffuse hepatic hemangiomatosis (DHH) in a 50-year-old male presented with acute painless jaundice of 10 days’ duration, dark urine, and hepatosplenomegaly. Laboratory workup revealed normocytic anemia, indirect hyperbilirubinemia, and elevated LDH levels, suggesting hemolysis, though the direct Coombs test was negative. Liver function tests showed cholestatic and hepatocellular injury patterns, while creatinine and coagulation profiles were initially normal. Abdominal ultrasound and triphasic computed tomography demonstrated hepatosplenomegaly and multiple hepatic focal lesions with peripheral nodular enhancement and centripetal fill-in. Liver biopsy revealed markedly dilated sinusoids without malignant infiltration. Unlikely, the patient developed acute kidney injury, hematemesis, and hepatic encephalopathy, culminating in death from liver failure within one month from the onset of his illness.