Impact of Human Genetic Variation on C-Reactive Protein Concentrations and Acute Appendicitis.

Background: Acute appendicitis is one of the most common abdominal emergencies worldwide. Both environmental and genetic factors contribute to the disease. C-reactive protein (CRP) is an important biomarker in the diagnosis of acute appendicitis. CRP concentrations are significantly affected by genetic variation. However, whether such genetic variation is causally related to appendicitis risk remains unclear. In this study, the causal relationship between single-nucleotide polymorphisms (SNPs) associated with circulating CRP concentrations and the risk and severity of acute appendicitis was investigated. Methods: CRP concentrations in serum of appendicitis patients (n = 325) were measured. Appendicitis was categorized as complicated/uncomplicated and gangrenous/non-gangrenous. Imputed SNP data (n = 287) were generated. A genome-wide association study (GWAS) on CRP concentrations and appendicitis severity was performed. Intersection and colocalization of the GWAS results were performed with appendicitis and CRP-associated loci from the Pan-UKBB cohort. A functional-genomics approach to prioritize genes was employed. Results: Thirteen percent of significant CRP quantitative trait loci (QTLs) that were previously identified in a large cohort of healthy individuals were replicated in our small patient cohort. Significant enrichment of CRP-QTLs in association with appendicitis was observed. Among these shared loci, the two top loci at chromosomes 1q41 and 8p23.1 were characterized. The top SNP at chromosome 1q41 is located within the promoter of H2.0 Like Homeobox (HLX) gene, which is involved in blood cell differentiation, and liver and gut organogeneses. The expression of HLX is increased in the appendix of appendicitis patients compared to controls. The locus at 8p23.1 contains multiple genes, including cathepsin B (CTSB), which is overexpressed in appendix tissue from appendicitis patients. The risk allele of the top SNP in this locus also increases CTSB expression in the sigmoid colon of healthy individuals. CTSB is involved in collagen degradation, MHC class II antigen presentation, and neutrophil degranulation. Conclusions: The results of this study prioritize HLX and CTSB as potential causal genes for appendicitis and suggest a shared genetic mechanism between appendicitis and CRP concentrations.

Studying the clinical, radiological, histological, microbiological, and immunological evolution during the different COVID-19 disease stages using minimal invasive autopsy.

The WHO defines different COVID-19 disease stages in which the pathophysiological mechanisms differ. We evaluated the characteristics of these COVID-19 disease stages. Forty-four PCR-confirmed COVID-19 patients were included in a prospective minimal invasive autopsy cohort. Patients were classified into mild-moderate (n = 4), severe-critical (n = 32) and post-acute disease (n = 8) and clinical, radiological, histological, microbiological and immunological data were compared. Classified according to Thoracic Society of America, patients with mild-moderate disease had no typical COVID-19 images on CT-Thorax versus 71.9% with typical images in severe-critical disease and 87.5% in post-acute disease (P < 0.001). Diffuse alveolar damage was absent in mild-moderate disease but present in 93.8% and 87.5% of patients with severe-critical and post-acute COVID-19 respectively (P = 0.002). Other organs with COVID-19 related histopathological changes were liver and heart. Interferon-γ levels were significantly higher in patients with severe-critical COVID-19 (P = 0.046). Anti-SARS CoV-2 IgG was positive in 66%, 40.6% and 87.5% of patients with mild-moderate, severe-critical and post-acute COVID-19 respectively (n.s.). Significant differences in histopathological and immunological characteristics between patients with mild-moderate disease compared to patients with severe-critical disease were found, whereas differences between patients with severe-critical disease and post-acute disease were limited. This emphasizes the need for tailored treatment of COVID-19 patients.

Organ-specific genome diversity of replication-competent SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not always confined to the respiratory system, as it impacts people on a broad clinical spectrum from asymptomatic to severe systemic manifestations resulting in death. Further, accumulation of intra-host single nucleotide variants during prolonged SARS-CoV-2 infection may lead to emergence of variants of concern (VOCs). Still, information on virus infectivity and intra-host evolution across organs is sparse. We report a detailed virological analysis of thirteen postmortem coronavirus disease 2019 (COVID-19) cases that provides proof of viremia and presence of replication-competent SARS-CoV-2 in extrapulmonary organs of immunocompromised patients, including heart, kidney, liver, and spleen (NCT04366882). In parallel, we identify organ-specific SARS-CoV-2 genome diversity and mutations of concern N501Y, T1027I, and Y453F, while the patient had died long before reported emergence of VOCs. These mutations appear in multiple organs and replicate in Vero E6 cells, highlighting their infectivity. Finally, we show two stages of fatal disease evolution based on disease duration and viral loads in lungs and plasma. Our results provide insights about the pathogenesis and intra-host evolution of SARS-CoV-2 and show that COVID-19 treatment and hygiene measures need to be tailored to specific needs of immunocompromised patients, even when respiratory symptoms cease.

The clinical value of minimal invasive autopsy in COVID-19 patients.

BACKGROUND: Minimally invasive autopsy (MIA) is a validated and safe method to establish the cause of death (COD), mainly in low-resource settings. However, the additional clinical value of MIA in Coronavirus disease (COVID-19) patients in a high-resource setting is unknown. The objective was to assess if and how MIA changed clinical COD and contributing diagnoses in deceased COVID-19 patients. METHODS AND FINDINGS: A prospective observational cohort from April to May 2020 in a 981-bed teaching hospital in the epicenter of the COVID-19 pandemic in Belgium was established. Patients who died with either PCR-confirmed or radiologically confirmed COVID-19 infection were consecutively included. MIA consisted of whole-body CT and CT-guided Tru-Cut® biopsies. Diagnostic modalities were clinical chart review, radiology, microbiology, and histopathology which were assessed by two independent experts per modality. MIA COD and contributing diagnoses were established during a multi-disciplinary meeting. Clinical COD (CCOD) and contributing diagnosis were abstracted from the discharge letter. The main outcomes were alterations in CCOD and contributing diagnoses after MIA, and the contribution of each diagnostic modality. We included 18 patients, of which 7 after intensive care unit hospitalization. MIA led to an alteration in 15/18 (83%) patients. The CCOD was altered in 5/18 (28%) patients. MIA found a new COD (1/5), a more specific COD (1/5), a less certain COD (1/5), or a contributing diagnosis to be the COD (2/5). Contributing diagnoses were altered in 14/18 (78%) patients: 9 new diagnoses, 5 diagnoses dismissed, 3 made more specific, and 2 made less certain. Overall, histopathology contributed in 14/15 (93%) patients with alterations, radiology and microbiology each in 6/15 (40%), and clinical review in 3/15 (20%). Histopathology was deemed the most important modality in 10 patients, radiology in two patients, and microbiology in one patient. CONCLUSION: MIA, especially histological examination, can add valuable new clinical information regarding the cause of death in COVID-19 patients, even in a high-resource setting with wide access to premortem diagnostic modalities. MIA may provide important clinical insights and should be applied in the current ongoing pandemic. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04366882.

An observational study of innate immune responses in patients with acute appendicitis.

Acute appendicitis is a common surgical emergency worldwide. Exaggerated immune responses could be associated with appendicitis. This study aimed at characterizing immune responses towards a large variety of gut commensals and pathogens, and pattern recognition receptor (PRR) ligands, and investigating the course of systemic inflammation in a prospective cohort of acute appendicitis patients. PBMC responses of 23 patients of the cohort and 23 healthy controls were characterized more than 8 months post-surgery. Serum cytokine levels were measured in 23 patients at the time of appendicitis and after one month. CRP, WBC and percentage of neutrophils were analyzed in the total cohort of 325 patients. No differences in PBMC responses were found between patients and controls. Stronger IL-10 responses were found following complicated appendicitis. A trend towards lower IL-8 responses was shown following gangrenous appendicitis. Serum IL-10 and IL-6 were significantly elevated at presentation, and IL-6, IL-8 and TNF-α levels were higher in complicated appendicitis. Routine biomarkers could predict severity of appendicitis with high specificities, but low sensitivities. Cytokine responses in patients following acute appendicitis did not differ from healthy controls. Higher serum cytokine levels were found in acute complicated and gangrenous cases. Further research into discriminative biomarkers is warranted.

Selective abdominal venous congestion induces adverse renal and hepatic morphological and functional alterations despite a preserved cardiac function.

Venous congestion is an important contributor to worsening renal function in heart failure and the cardiorenal syndrome. In patients, it is difficult to study the effects of isolated venous congestion on organ function. In this study, the consequences of isolated abdominal venous congestion on morphology and function of the kidneys, liver and heart were studied in a rat model. Twelve sham-operated (SHAM) male Sprague Dawley rats were compared to eleven inferior vena cava-constricted (IVCc) rats for twenty-one weeks. Abdominal venous pressure was significantly higher in the IVCc versus SHAM group (p < 0.0001). Indices of liver and kidney weight, function and morphology, inflammation as well as collagen deposition were significantly increased in the IVCc compared to SHAM group, (p < 0.05). Echocardiographic and hemodynamic parameters were largely unaffected by abdominal venous congestion. In this rat model of isolated abdominal venous congestion, retrogradely conducted glomerular hypertension without a concomitant change in glomerular filtration rate was observed. Adverse short-term hepatic morphological alterations were developed which explain the observed organ function dysfunction. Importantly, cardiac function remained comparable between both groups. This study provides relevant insight in the pathophysiology of abdominal congestion on organ function.

Validation and Application of a Custom-Designed Targeted Next-Generation Sequencing Panel for the Diagnostic Mutational Profiling of Solid Tumors.

The inevitable switch from standard molecular methods to next-generation sequencing for the molecular profiling of tumors is challenging for most diagnostic laboratories. However, fixed validation criteria for diagnostic accreditation are not in place because of the great variability in methods and aims. Here, we describe the validation of a custom panel of hotspots in 24 genes for the detection of somatic mutations in non-small cell lung carcinoma, colorectal carcinoma and malignant melanoma starting from FFPE sections, using 14, 36 and 5 cases, respectively. The targeted hotspots were selected for their present or future clinical relevance in solid tumor types. The target regions were enriched with the TruSeq approach starting from limited amounts of DNA. Cost effective sequencing of 12 pooled libraries was done using a micro flow cell on the MiSeq and subsequent data analysis with MiSeqReporter and VariantStudio. The entire workflow was diagnostically validated showing a robust performance with maximal sensitivity and specificity using as thresholds a variant allele frequency >5% and a minimal amplicon coverage of 300. We implemented this method through the analysis of 150 routine diagnostic samples and identified clinically relevant mutations in 16 genes including KRAS (32%), TP53 (32%), BRAF (12%), APC (11%), EGFR (8%) and NRAS (5%). Importantly, the highest success rate was obtained when using also the low quality DNA samples. In conclusion, we provide a workflow for the validation of targeted NGS by a custom-designed pan-solid tumor panel in a molecular diagnostic lab and demonstrate its robustness in a clinical setting.

Non-hodgkin lymphoma after treatment with extended dosing temozolomide and radiotherapy for a glioblastoma: a case report.

Temozolomide (TMZ) is an alkylating agent, used for the treatment of high-grade gliomas. This case report describes the development of a non-Hodgkin lymphoma in a patient treated with extended-dose temozolomide and radiotherapy. In addition to the possible mutagenic effect of temozolomide - as described for all alkylating agents - there might have been an immunosuppressive effect of TMZ. The pathological appearance of the lymphoma as well as the presence of a grade 3 lymphopenia early in treatment supports this hypothesis. As the use of TMZ increases, the awareness that TMZ may induce secondary malignancies should increase as well.

Density and distribution of connexin 43 in corpus cavernosum tissue from diabetic and hypogonadal patients with erectile dysfunction.

AIM: Altered expression of connexin 43 (Cx43) has been postulated to be involved in the development and progression of various diseases including erectile dysfunction (ED). The aim of this study was to determine whether distribution and density of the gap junction protein Cx43 are altered in human corpus cavernosum (HCC) tissue samples derived from diabetic or hypogonadal patients with ED compared to those from normal subjects. METHODS: HCC tissue sections derived from normal, diabetic and hypogonadal subjects were fixed in 4% formaldehyde, embedded in paraffin and immunostained with a monoclonal mouse anti-rat Cx43 antibody. Cx43 density was expressed as the cumulative number of gap junction plaques per unit area of tissue corrected for number of 4',6-diamidino-2-phenylindole, dihydrochloride-labeled smooth muscle cells (dots per unit area corrected for number of cells). RESULTS: The distribution of Cx43 plaques in smooth muscle was not affected in tissues derived from diabetic or hypogonadal subjects with ED compared with those from normal subjects. However, the number of Cx43 plaques was significantly reduced in HCC tissues derived from diabetic or hypogonadal subjects (73 ± 8% and 68 ± 11% of normal, respectively), indicating reduced Cx43 gap junctions in diabetic and hypogonadal subjects with ED. CONCLUSIONS: Cx43 density in the HCC was diminished in tissue samples derived from diabetic or hypogonadal patients with ED compared to tissue samples from normal non-diabetic subjects. This marked decrease in Cx43 gap junction channels may contribute to attenuated gap junction function and to diminished erectile physiology.

A new algorithm in patients with elevated and/or rising prostate-specific antigen level, minor lower urinary tract symptoms, and negative multisite prostate biopsies.

Patients with elevated and/or rising prostate-specific antigen (PSA), minor lower urinary tract symptoms (LUTS), and no evidence for prostate cancer on (multiple) extended prostate biopsies are a regularly encountered problem in urological practice. Even now, patients are seen with no objective explanation of this persistent elevated and/or rising PSA. So far, many strategic proposals have been elaborated and published to deal with this specific population including the use of different PSA derivates; applying different biopsy schemes--strategies--biopsy target imaging; diagnostic use of prostate cancer genes; and many more. In this review, we propose a new algorithm in which an urodynamic evaluation should be included since bladder outlet obstruction (BOO) can be expected. Once BOO is confirmed, a transurethral resection of the prostate (TURP) can be offered to these patients. This procedure will result in subjective and biochemical improvement and allows extensive histological examination. Current literature was reviewed with regard to this specific population. This research was performed using the commercially available Medline online search tools and applying the following search terms: "diagnostic TURP"; "elevated PSA"; and "prostate biopsy". Furthermore, subsequent reference search was executed on retrieved articles.

Long-term clinical outcome of diagnostic transurethral resection of the prostate in patients with elevated prostate-specific antigen level and minor lower urinary tract symptoms.

INTRODUCTION: In patients with minor lower urinary tract symptoms (LUTS), elevated prostate-specific antigen (PSA) levels and (multiple) negative multi-site biopsies, therapy decision is complex. Long-term outcome of a diagnostic transurethral resection of the prostate (TURP) in these patients needs to be determined. METHODS: We retrospectively evaluated patients with minor LUTS, elevated PSA levels (>or=4 ng/ml) and no signs of prostate cancer. Patients with bladder outlet obstruction (BOO) underwent TURP. When TURP showed no malignancy, patients were annually evaluated by PSA testing and the International Prostate Symptom Score (IPSS). RESULTS: The study included 82 consecutive patients satisfying the inclusion criteria. All patients underwent TURP. No malignancy was encountered in 74 patients (90.2%). Of this group, 36 patients were followed >3 years (mean 62.1 months). One patient (2.8%) showed a persistently rising PSA level with positive extended multi-site biopsies 4 years after TURP, implying further treatment. 35 patients (97.2%) had a permanent complete normalization of PSA levels (<4 ng/ml) together with normalized IPSS. CONCLUSIONS: We consider an elevated PSA level in patients with minor LUTS and (multiple) negative multi-site biopsies as a sign of BOO. If these patients receive a diagnostic TURP, long-term outcome is excellent.

Prospective study of the role of transurethral resection of the prostate in patients with an elevated prostate-specific antigen level, minor lower urinary tract symptoms, and proven bladder outlet obstruction.

BACKGROUND: Deciding on strategy for patients with minor lower urinary tract symptoms (LUTS), elevated prostate-specific antigen (PSA) levels, unsuspicious digital rectal examination (DRE) and/or transrectal ultrasound (TRUS), and multiple negative extended prostate biopsies is complex. OBJECTIVES: To define the role and clinical significance of transurethral resection of the prostate (TURP) in these patients. DESIGN, SETTINGS, AND PARTICIPANTS: Thirty-three patients with elevated PSA; minor LUTS, as assessed by the International Prostate Symptoms Score (IPSS); no suspicion for prostate cancer on DRE and/or TRUS; and negative extended prostate biopsies were prospectively enrolled in a cohort study at a tertiary care institution. INTERVENTION: After full urodynamic investigation showing all patients to be bladder outlet obstructed, TURP was performed. MEASUREMENTS: Resected tissue was histologically examined for presence of prostate cancer. Within 6 mo after TURP, patients were clinically reevaluated by means of IPSS and PSA level. RESULTS AND LIMITATIONS: Preoperatively, mean PSA and IPSS values were 8.2ng/ml and 6.8, respectively. Mean detrusor pressure at maximum flow was 80.3cm H(2)O. Histological examination after TURP revealed benign prostate hyperplasia in 81.8% (subgroup 1) and aggressive prostate cancer in 6.1% of patients (subgroup 2). In 12.1% of patients, only a few chips of nonaggressive prostate cancer (T1a) were detected. In patients without signs of aggressive prostate cancer (93.9%=12.1%+81.8%, subgroup 3), mean postoperative PSA and IPSS values were 0.6ng/ml and 2.4, respectively, while these values were 0.6ng/ml and 2.5ng/ml in subgroup 1 (p<0.0001). This study is limited in sample size, requiring more research to confirm these results. CONCLUSIONS: This prospective study shows that, in patients with minor LUTS and no suspicion for prostate cancer, bladder outlet obstruction can result in elevated PSA levels. These patients will benefit from TURP regarding symptomatology and supernormalisation of PSA levels. Moreover, albeit in few cases, histological examination will reveal aggressive prostate cancer.

Aortic valve lymphoma presenting as acute coronary syndrome.

Primary cardiac lymphoma is a very rare tumor which commonly affects the right atrium, although any chamber may be affected. Over the past few decades, the incidence of the lesion has increased, due mainly to growing numbers of immunocompromised patients, either HIV-related or iatrogenic. Because of this rapid evolution, the situation represents an oncologic emergency, and therefore early diagnosis and treatment are crucial. Although MRI is the most sensitive modality, open biopsy remains the 'gold standard' for reaching the diagnosis. However, the overall prognosis is poor. Herein is presented a case of a large B-cell non-Hodgkin lymphoma involving only the aortic valve.

Clinical relevance of transurethral resection of the prostate in "asymptomatic" patients with an elevated prostate-specific antigen level.

OBJECTIVES: To determine the clinical relevance of transurethral resection of the prostate (TURP) in patients with minor lower urinary tract symptoms (LUTS) but elevated prostate-specific antigen (PSA) levels. METHODS: We retrospectively included 82 patients, aged 50.2-78.2 yr, with minor LUTS, elevated PSA (> or =4 ng/ml), and no signs of prostate cancer (PCa) after (multiple) negative multisite biopsies who underwent TURP after they were diagnosed by urodynamics with bladder outlet obstruction (BOO). We evaluated the clinical benefit of TURP by assessing its effect on International Prostate Symptom Score (IPSS) and PSA and the diagnostic value of histologic examination of the resected tissue for the presence of PCa. RESULTS: After TURP, histologic analysis of the resected specimen revealed that eight patients (9.8%) had PCa; seven of these patients had a tumour that needed further treatment. The remaining 74 patients (90.2%) were diagnosed with BOO due to benign prostatic hyperplasia/benign prostatic enlargement (BPH/BPE). In this group, the mean PSA level decreased from 8.8 ng/ml before TURP to 1.1 ng/ml in the first year and 1.3 ng/ml in the second year after TURP; the mean IPSS decreased from 8.8 to 1.5 in the first year after TURP. CONCLUSIONS: The current data suggest that patients with minor LUTS and elevated PSA without evidence of PCa are very likely to have BOO due to BPH/BPE and may benefit from TURP if obstruction is proved. However, a prospective trial is warranted to assess the impact of these results on clinical practice.

Metanephric adenoma during pregnancy: clinical presentation, histology, and cytogenetics.

Metanephric adenoma is a rare benign tumor of the kidney. It is considered to be derived from embryonic renal tissue and to be the benign counterpart of the Wilms tumor. Although its imaging findings and immunohistochemistry are nonspecific, it has a typical microscopic morphology. We describe a case of a 24-year-old primigravida who presented in the 28th week of pregnancy with lower back pain, fever, malaise, and anemia. At renal ultrasonography and magnetic resonance imaging, a hemorrhagic tumor of 10 cm in diameter originating from the right kidney was seen. Based on the imaging findings, the diagnosis of a cystic renal cell carcinoma with recent hemorrhage was suggested, and a radical nephrectomy was performed. Pathologic examination concluded to a metanephric adenoma. The further pregnancy went on well. The karyotype of the tumor was 46,XX,t(1;22)(q22;q13),t(15;16)(q21;p13). To our knowledge, this is the first report on these chromosomal abnormalities in metanephric adenoma.

Large cleaved and immunoblastic lymphoma may represent two distinct clinicopathologic entities within the group of diffuse large B-cell lymphomas.

PURPOSE: The reliability of immunohistochemistry for subdividing diffuse large B-cell lymphomas (DLBCL) into germinal center B-cell-like (GCB) and non-GCB prognostic subgroups is debated. In this study we evaluated the prognostic significance of such subgrouping on a series of 153 DLBCL patients. Furthermore, we investigated whether both subgroups could comprise clinicopathologic entities recognized by their morphology and characterized by a distinct phenotype, specific genetic abnormalities, and clinical characteristics. PATIENTS AND METHODS: All samples from patients were reviewed and morphologically subdivided into large cleaved, immunoblastic, and not otherwise specified DLBCL. GCB and non-GCB immunohistochemical profiles were established. The presence of chromosomal translocations involving BCL2, BCL6, and MYC and/or rearrangements of these genes was investigated. RESULTS: Subdividing DLBCL with either a GCB or non-GCB immunophenotypic profile was not of prognostic significance. Nevertheless, CD10 expression was a predictor of favorable outcome, whereas high bcl-2 expression and BCL6 rearrangement were adverse predictors of disease-free survival. Interestingly, large cleaved DLBCL was clearly associated with a GCB immunophenotypic profile, CD10 expression, BCL2 rearrangement, age younger than 60 years, and low to low/intermediate International Prognostic Index risk, but was not of prognostic significance. In contrast, immunoblastic morphology was associated with a non-GCB profile and was a significant predictor of unfavorable DFS. CONCLUSION: Subdividing DLBCL into subgroups based on their immunohistochemical profile was not of prognostic significance. Nevertheless, it allowed the additional characterization of two lymphoma subgroups previously recognized in the Working Formulation. Both correspond to two distinct clinicopathologic entities within the DLBCL.

Use of liquid-based cytology in serous fluids: a comparison with conventional cytopreparatory techniques.

OBJECTIVE: To examine the performance of liquid-based cytology (LBC) on body cavity fluids as compared with conventional cytopreparatory techniques. STUDY DESIGN: Slides from a total of 592 serous fluids, effusions as well as intraoperative washings, were reviewed. Of these fluids, 301 were collected before and 291 after the introduction of the PrepStain LBC (TriPath Imaging, Burlington, North Carolina, U.S.A.) in our laboratory. RESULTS: PrepStain thin layers showed excellent morphology on a clear background, with preservation of 3-dimensional configurations and a sufficient amount of extracellular material to allow an accurate diagnosis. Cytopreparation, screening and interpretation of LBC were less time consuming. Moreover, when the performance of the various cytopreparatory techniques in malignant fluids was studied, PrepStain thin layers excelled over conventional cytopreparatory methods in showing a significantly lower false negative rate (P=.0414). CONCLUSION: Our findings indicate that in body fluid cytology, thin layers can safely replace other types of wet-fixed preparations, resulting in enhanced specimen quality and diminished false negative rates.

Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease.

In animals, the combination of oxidative liver damage and inhibited hepatocyte proliferation increases the numbers of hepatic progenitors (oval cells). We studied different murine models of fatty liver disease and patients with nonalcoholic fatty liver disease or alcoholic liver disease to determine whether oval cells increase in fatty livers and to clarify the mechanisms for this response. To varying degrees, all mouse models exhibit excessive hepatic mitochondrial production of H(2)O(2), a known inducer of cell-cycle inhibitors. In mice with the greatest H(2)O(2) production, mature hepatocyte proliferation is inhibited most, and the greatest number of oval cells accumulates. These cells differentiate into intermediate hepatocyte-like cells after a regenerative challenge. Hepatic oval cells are also increased significantly in patients with nonalcoholic fatty liver disease and alcoholic liver disease. In humans, fibrosis stage and oval cell numbers, as well as the number of intermediate hepatocyte-like cells, are strongly correlated. However, cirrhosis is not required for oval cell accumulation in either species. Rather, as in mice, progenitor cell activation in human fatty liver diseases is associated with inhibited replication of mature hepatocytes. The activation of progenitor cells during fatty liver disease may increase the risk for hepatocellular cancer, similar to that observed in the Solt-Farber model of hepatocarcinogenesis in rats.