Repair of cirrhotic livers occurs, in part, by repopulation with hepatocytes through the stem/progenitor pathway. There remain many uncertainties regarding this pathway. Hepatocyte “buds” occurring ...in broad septa are hypothesized to be the anatomic manifestation of this pathway. Our purpose was to define a morphologic sequence of bud maturation to allow a quantitative measure of the importance of the stem/progenitor pathway in humans. Histologic sections from 37 liver resection specimens were stained with trichrome, epithelial cell adhesion molecule (EpCAM), K19, CD34, glutamine synthetase (GS), and Ki‐67. Specimens were stratified by etiology (10 biliary, 22 nonbiliary, five controls) and stage. Buds were defined as clusters of hepatocytes within septa. Five levels of bud maturation (0‐4) were defined by the progressive increase in hepatocyte progeny relative to cholangiocytes. Level 0 single‐cell buds are K19+/GS+/EpCAM+/Heppar1−. In level 1, the progeny are morphologically hepatocytes (K19−/GS+/EpCAM+/Heppar1+). In level 2‐4 buds, hepatocytes increase and become progressively GS− and EpCAM−. Associated endothelium is CD34+ in level 1‐2 buds and becomes CD34− near hepatic veins in level 3‐4 buds. Progeny of the bud sequence may represent up to 70% of hepatocytes (immaturity index of 70%). In biliary disease, bud number is reduced in association with duct loss and cholestatic destruction of nascent buds. Conclusions: The stem/progenitor pathway, manifested anatomically by the bud sequence, is a major mechanism for repopulation of cirrhotic livers. The bud sequence reveals some critical features of hepatic morphogenesis, including that 1) the majority of distal cholangiocytes have stem‐like properties, and 2) availability of bile ducts and/or venous drainage are limiting factors for regeneration. (Hepatology 2015;61:1696–1707)
Early detection of hepatocellular carcinoma (HCC) is critical for successful treatment. However, the differential diagnosis between HCC and benign hepatic lesions is sometimes difficult and new ...biochemical markers for HCC are required. It has been reported that glypican-3 (GPC3) messenger RNA (mRNA) is significantly increased in most HCCs compared with benign liver lesions or normal liver. The goal of this study is to determine whether GPC3 is also overexpressed at the protein level and whether GPC3 is detectable in the serum of patients with HCC.
GPC3 was assessed in liver tissue sections by immunohistochemistry and in serum by enzyme-linked immunosorbent assay. Serum α-fetoprotein (AFP) level was also measured in the same patients.
Immunohistochemical studies showed that GPC3 is expressed in 72% of HCCs (21 of 29), whereas it is not detectable in hepatocytes from normal liver and benign liver diseases. Consistent with this, GPC3 was undetectable in the serum of healthy donors and patients with hepatitis, but its levels were significantly increased in 18 of 34 patients (53%) with HCC. In addition, only 1 of 20 patients with hepatitis plus liver cirrhosis displayed elevated levels of serum GPC3. Interestingly, in most cases, there was no correlation between GPC3 and AFP values. Thus, at least 1 of the 2 markers was elevated in 82% of the patients with HCC.
GPC3 is specifically overexpressed in most HCCs and is elevated in the serum of a large proportion of patients with HCC. The simultaneous determination of GPC3 and AFP may significantly increase the sensitivity for diagnosis of HCC.
Although the natural history of autoimmune hepatitis (AIH) has been characterized, little is known about patients who present asymptomatically. Consequently, whether they require immunosuppressive ...therapy with its associated complications is unclear. To compare the natural history of asymptomatic AIH with symptomatic AIH, a large cohort of patients from a single center was examined. All patients with a clinical diagnosis of AIH were reassessed using the revised criteria of the International Autoimmune Hepatitis Group. Liver histology, response to therapy, and survival were assessed. Patients asymptomatic at presentation (n = 31) had lower serum aminotransferase, bilirubin, and immunoglobulin G (IgG) values at baseline. Half of the asymptomatic patients received no therapy, and their survival was no different from that of the total cohort. Ten-year survival was 80.0% (62.5%-97.5%) in the asymptomatic group and 83.8% (75.1%-92.6%) in the symptomatic patients (P = NS). Survival to liver-related endpoints at 10 years was similar in both groups: 89.5% (75.7%-100%) asymptomatic and 83.8% (75.1%-92.6%) symptomatic patients (P = NS). Patients with cirrhosis at baseline had poorer 10-year survival (61.9% CI 44.9%-78.9%) than those without cirrhosis at presentation (94.0% CI 87.4%-100%) (P = .003) regardless of whether they presented with symptoms or whether they received immunosuppressive therapy. In conclusion, patients with AIH who are asymptomatic at presentation have a good prognosis and may not require immunosuppressive therapy. Cirrhosis on initial liver biopsy portends a poor prognosis in all patients with AIH.
Background & Aims
In normal human liver, glutamine synthetase (GS) is expressed in a rim of hepatocytes surrounding hepatic veins. GS expression is decreased in cirrhosis and increased in chronic ...hepatitis, focal nodular hyperplasia, peritumoural hyperplasia and some hepatocellular neoplasms. For the non‐neoplastic conditions, there is limited information available on histological pattern of altered GS expression and the mechanisms of these changes.
Methods
We examined GS expression in 58 large specimens and 45 needle biopsies with a variety of non‐neoplastic human liver conditions and in 12 normal control livers. Expression was correlated with clinical and histological disease states.
Results
We identified four patterns of GS expression: (i) Loss of normal perivenular expression was seen in states of chronic congestion, severe cirrhosis and zone 3 necrosis. (ii) Diffuse expression was seen in states with active hepatocellular injury and correlated with Ki‐67 expression. (iii) Interface expression was seen in feathery degeneration of chronic cholestasis. (iv) GS expression in activated hepatocyte progenitor cells (HPCs) associated with small ducts and ductules was seen in fulminant hepatic failure and in early and late chronic liver disease and rarely in normal livers.
Conclusions
Glutamine synthetase expression is increased in regenerating hepatocytes and in early HPCs prior to morphological evidence of hepatocellular differentiation. This may be the earliest marker of HPCs yet demonstrated. Loss of expression may be a reflection of disrupted endothelium‐hepatocyte contact in hepatic vein walls caused by congestive injury as found in congestive heart failure and advanced cirrhosis.
Backgrounds & Aims The clinical severity of cirrhosis varies widely. We investigated whether histological sub-classification of cirrhosis using the Laennec system can discriminate different outcomes ...among patients with cirrhosis. Methods One hundred and seventy-five patients with chronic liver disease who underwent liver biopsy and showed stage 3 or 4 fibrosis between January 2001 and December 2008 were prospectively enrolled. Cirrhosis was sub-classified into three groups (4A, 4B, and 4C) according to the Laennec system. The end point was liver-related event (LRE) occurrence, including decompensation, hepatocellular carcinoma, and liver-related death. Results The median age of the patients (110 men, 65 women) was 55 years. Stages 3, 4A, 4B, and 4C were identified in 46 (26.3%), 16 (9.1%), 82 (46.9%), and 31 (17.7%) patients, respectively. During the follow-up period, LREs occurred in 32 (18.3%) patients: 4 (8.7%) with stage 3, 2 (12.5%) with stage 4A, 17 (20.7%) with stage 4B, and 9 (29.0%) with stage 4C. In a multivariate analysis, histological sub-classification of cirrhosis independently predicted LRE occurrence. While patients with stage 4A tended to be at higher risk of LRE occurrence than those with stage 3, patients with stages 4B and 4C had significantly higher risks of LRE occurrence, with hazard ratios of 6.158 ( p = 0.016) and 8.945 ( p = 0.004), respectively. Conclusions Histological sub-classification of cirrhosis using the Laennec system can be used to assess the risk of LRE occurrence among patients with cirrhosis. Our study provides a solid basis for further studies of non-invasive methods for monitoring the risk of LRE occurrence and will help physicians to establish optimum treatment strategies.
Fatty liver disease involves the accumulation of triglycerides in hepatocytes, necrosis of hepatocytes, inflammation, and often fibrosis with progression to cirrhosis. The two-hit model summarizes ...the important early metabolic events leading to hepatocellular necrosis in nonalcoholic steatohepatitis (NASH). In this article, we provide evidence of lipid release from hepatocytes in posttransplant fat necrosis and in NASH and quantify vascular obliteration in a series of biopsies with NASH. Obliteration of small hepatic veins (<30 microm) in small numbers is compensated by collateral flow. Obliteration of larger hepatic veins (>30 microm) is associated with fibrotic collapse lesions that are not easily resorbed. Based on these observations, we propose a new four-step model that includes the later events that lead to cirrhosis after necrosis has occurred. This model is applicable to nonalcoholic fatty liver disease (NAFLD), alcoholic disease, postjejunoileal bypass disease, and posttransplant fat necrosis. The first step is steatosis facilitated by insulin, and the second is necrosis induced by intracellular lipid toxicity or lipid peroxidation, or both, modified by alcohol, drugs, and ischemia. The third step is release of bulk lipid from hepatocytes into the interstitium leading to direct and inflammatory injury to hepatic veins. The fourth step is venous obstruction with secondary collapse and ultimately fibrous septation and cirrhosis.
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