Laparoscopy and laparotomy combined with bone marrow biopsy in staging Hodgkin's disease.

The relative merits of laparoscopy with liver and spleen biopsy and staging laparotomy were studied in 91 unselected patients with Hodgkin''s disease. Laparoscopy with liver and spleen biopsy were combined with needle biopsy of the bone marrow and laparotomy was combined with open bone marrow biopsy. In 65 untreated patients six out of seven with liver or marrow disease, or both, were shown to have extranodal lymphomas in these sites by laparoscopy plus needle marrow biopsy. Among 26 patients who had been treated this finding occurred in six out of 10 patients. Spleen biopsies during laparoscopy detected infiltration by lymphoma in 14 out of 37 (38%) patients with diseases spleens. Morbidity was higher after laparotomy than after laparoscopy. Laparoscopy produced abdominal bleeding secondary to splenic biopsy in two patients. All patients with Hodgkin''s disease should be subjected to laparoscopy plus needle marrow biopsy before undergoing laparotomy.     

Comparison of Histologic Characteristics of Chinese Chronic Hepatitis B Patients with Persistently Normal or Mildly Elevated ALT

Liver disease can develop in chronic hepatitis B (CHB) patients with normal or mildly elevated alanine aminotransferase (ALT) who seldom undergo liver biopsy. We aimed to determine histologic characteristics of a large cohort of Chinese CHB patients undergoing liver biopsy and to evaluate the utility of ALT and HBV DNA values at the time of biopsy in predicting liver disease in this population. This prospective study enrolled 230 treatment-naïve patients with persistently normal or mildly elevated ALT. All patients had a liver biopsy. ALT, aspartate aminotransferase (AST), and HBV DNA levels were some of the other parameters measured. Using Scheuer''s classification, significant histology was defined as stage ≧2 fibrosis and/or stage 1 fibrosis plus≧ grade 2 inflammation. Liver disease was observed in 34.4% and 61.8% of patients with normal ALT and mildly elevated ALT, respectively. Patients with mildly elevated ALT levels had significantly more events, including liver disease, elevated AST, and moderate to severe inflammation and liver fibrosis, than patients with normal ALT (all P≤0.005). A total of 107 patients (46.5%) had liver disease and 123 (53.5%) did not. PLT and ALT were significantly associated with liver disease (both P<0.001). Patients with elevated ALT, lower platelet count and HBV DNA < 7 log₁₀copies/mL may have histologically significant changes associated with liver disease. Multivariate analysis showed that PLT and HBV DNA levels were significantly associated with liver disease in patients with normal ALT while gender and HBV DNA levels were significantly associated with liver disease in patients with mildly elevated ALT. Assessing liver damage via biopsy in patients with normal or mildly elevated ALT may help to identify those who would benefit from antiviral therapy.     

Tuberculous pseudotumour of the liver developing during antituberculous chemotherapy.

A 29-year-old Chinese woman presented with a liver mass 2 months after initiation of chemotherapy for disseminated tuberculosis. A percutaneous liver biopsy revealed tuberculous pseudotumour. Although acid-fast bacilli were seen in the biopsy specimen, no organism could be cultured. No changes were made in the antituberculous chemotherapy, and the mass subsequently resolved. The patient was still well 18 months after presentation. To the authors'' knowledge, the features of tuberculous pseudotumour seen with ultrasonography and computerized tomography have not previously been described, nor has this condition previously been reported in patients already receiving antituberculous chemotherapy.     

Is MR Spectroscopy Really the Best MR-Based Method for the Evaluation of Fatty Liver in Diabetic Patients in Clinical Practice?

Objective

To investigate if magnetic resonance spectroscopy (MRS) is the best Magnetic Resonance (MR)-based method when compared to gradient-echo magnetic resonance imaging (MRI) for the detection and quantification of liver steatosis in diabetic patients in the clinical practice using liver biopsy as the reference standard, and to assess the influence of steatohepatitis and fibrosis on liver fat quantification.

Methods

Institutional approval and patient consent were obtained for this prospective study. Seventy-three patients with type 2 diabetes (60 women and 13 men; mean age, 54±9 years) underwent MRI and MRS at 3.0 T. The liver fat fraction was calculated from triple- and multi-echo gradient-echo sequences, and MRS data. Liver specimens were obtained in all patients. The accuracy for liver fat detection was estimated by receiver operator characteristic (ROC) analysis, and the correlation between fat quantification by imaging and histolopathology was analyzed by Spearman''s correlation coefficients.

Results

The prevalence of hepatic steatosis was 92%. All gradient-echo MRI and MRS findings strongly correlated with biopsy findings (triple-echo, rho = 0.819; multi-echo, rho = 0.773; MRS, rho = 0.767). Areas under the ROC curves to detect mild, moderate, and severe steatosis were: triple-echo sequences, 0.961, 0.975, and 0.962; multi-echo sequences, 0.878, 0.979, and 0.961; and MRS, 0.981, 0.980, and 0.954. The thresholds for mild, moderate, and severe steatosis were: triple-echo sequences, 4.09, 9.34, and 12.34, multi-echo sequences, 7.53, 11.75, and 15.08, and MRS, 1.71, 11.69, and 14.91. Quantification was not significantly influenced by steatohepatitis or fibrosis.

Conclusions

Liver fat quantification by MR methods strongly correlates with histopathology. Due to the wide availability and easier post-processing, gradient-echo sequences may represent the best imaging method for the detection and quantification of liver fat fraction in diabetic patients in the clinical practice.     

Quantification of liver fibrosis via second harmonic imaging of the Glisson's capsule from liver surface

Liver surface is covered by a collagenous layer called the Glisson's capsule. The structure of the Glisson's capsule is barely seen in the biopsy samples for histology assessment, thus the changes of the collagen network from the Glisson's capsule during the liver disease progression are not well studied. In this report, we investigated whether non‐linear optical imaging of the Glisson's capsule at liver surface would yield sufficient information to allow quantitative staging of liver fibrosis. In contrast to conventional tissue sections whereby tissues are cut perpendicular to the liver surface and interior information from the liver biopsy samples were used, we have established a capsule index based on significant parameters extracted from the second harmonic generation (SHG) microscopy images of capsule collagen from anterior surface of rat livers. Thioacetamide (TAA) induced liver fibrosis animal models was used in this study. The capsule index is capable of differentiating different fibrosis stages, with area under receiver operating characteristics curve (AUC) up to 0.91, making it possible to quantitatively stage liver fibrosis via liver surface imaging potentially with endomicroscopy.

     

Diagnostic Performance of a Rapid Magnetic Resonance Imaging Method of Measuring Hepatic Steatosis

Objectives

Hepatic steatosis is associated with an increased risk of developing serious liver disease and other clinical sequelae of the metabolic syndrome. However, visual estimates of steatosis from histological sections of biopsy samples are subjective and reliant on an invasive procedure with associated risks. The aim of this study was to test the ability of a rapid, routinely available, magnetic resonance imaging (MRI) method to diagnose clinically relevant grades of hepatic steatosis in a cohort of patients with diverse liver diseases.

Materials and Methods

Fifty-nine patients with a range of liver diseases underwent liver biopsy and MRI. Hepatic steatosis was quantified firstly using an opposed-phase, in-phase gradient echo, single breath-hold MRI methodology and secondly, using liver biopsy with visual estimation by a histopathologist and by computer-assisted morphometric image analysis. The area under the receiver operating characteristic (ROC) curve was used to assess the diagnostic performance of the MRI method against the biopsy observations.

Results

The MRI approach had high sensitivity and specificity at all hepatic steatosis thresholds. Areas under ROC curves were 0.962, 0.993, and 0.972 at thresholds of 5%, 33%, and 66% liver fat, respectively. MRI measurements were strongly associated with visual (r² = 0.83) and computer-assisted morphometric (r² = 0.84) estimates of hepatic steatosis from histological specimens.

Conclusions

This MRI approach, using a conventional, rapid, gradient echo method, has high sensitivity and specificity for diagnosing liver fat at all grades of steatosis in a cohort with a range of liver diseases.     

Krabbe's disease: globoid cell leukodystrophy

The clinical features of regression in mental and motor development of a 7-month-old child are reported, together with the demonstration of a profound deficiency of galactosylceramide beta-D-galactosidase in a liver biopsy. The diagnosis of Krabbe''s disease or globoid cell leukodystrophy (GLD) is therefore unequivocally established. The clinical features and morbid anatomical findings permitting the diagnosis of GLD in two of the child''s sibs are summarized. This is the first report from Newfoundland of this inborn error of sphingolipid metabolism.     

Wilson's disease: a common liver disorder?

In two sibships 7 of 24 siblings were homozygous for Wilson''s disease. In family A, the largest kindred of this recessively inherited disease thus far reported, the proband presented with chronic active hepatitis, one sibling died of cirrhosis, a second had clinical evidence of chronic liver disease and two others had biochemical and histologic changes in liver biopsy specimens. In family B the proband had cirrhosis and portal hypertension and one sibling had biochemical and histologic evidence of liver disease. All six living patients had low serum concentrations of ceruloplasmin and copper and a high 24-hour urinary excretion of copper, which was greatly increased by administration of D-penicillamine. None showed neurologic abnormalities and only one had Kayser-Fleischer rings (detectable only by slit-lamp examination). Each patient had an erythrocyte sedimentation rate (ESR) of 8 mm/h or less. After 3 and 2 years, respectively, of D-penicillamine therapy the conditions of the two probands had improved. Liver function became normal in three siblings, and no abnormalities developed in the remaining one. Thus, since Wilson''s disease may present with chronic active hepatitis or cirrhosis with a normal ESR and without ocular or neurologic signs, it may be a more common cause of liver disease in young people than has been appreciated.     

Telocytes in human liver fibrosis

Liver fibrosis is a wound‐healing response which engages a variety of cell types to encapsulate injury. Telocyte (TC), a novel type of interstitial cell, has been identified in a variety of tissues and organs including liver. TCs have been reported to be reduced in fibrotic areas after myocardial infarction, human interstitial wall's fibrotic remodelling caused either by ulcerative colitis or Crohn's disease, and skin of systemic sclerosis. However, the role of TCs in human liver fibrosis remains unclear. Liver samples from human liver biopsy were collected. All samples were stained with Masson's trichrome to determine fibrosis. TCs were identified by several immunofluorescence stainings including double labelling for CD34 and c‐kit/CD117, or vimentin, or PDGF Receptor‐α, or β. We found that hepatic TCs were significantly decreased by 27%–60% in human liver fibrosis, suggesting that loss of TCs might lead to the altered organization of extracellular matrix and loss the control of fibroblast/myofibroblast activity and favour the genesis of fibrosis. Adding TCs might help to develop effective and targeted antifibrotic therapies for human liver fibrosis.     

Cirrhosis Associated with the Australia Antigen in an Infant Who Acquired Hepatitis from Her Mother

A 19-week-old English girl developed acute viral hepatitis, which became chronic with persistent hepatosplenomegaly and abnormal liver function tests. Liver biopsy at 1 year showed an active cirrhosis with multinucleated giant cells. The Australia (Au) antigen was detected repeatedly in the infant''s serum by immunodiffusion and by electron microscopy at the time of the acute attack and during the development of cirrhosis. She had apparently acquired the hepatitis from her mother, who had had jaundice at the end of pregnancy and for one month thereafter, and who was subsequently shown to be a carrier of Au antigen. Particles with surface projections resembling paramyxoviruses were observed in two of the later specimens of the infant''s serum.     

Detection of HCV-RNA in liver tissue does not correlate with inflammatory process and fibrosis activity in chronic hepatitis C

The significance of HCV-RNA presence in the liver tissue in chronic hepatitis C activity or prognosis has not yet been clearly explained. Therefore, we have examined the relationship between the presence of HCV-RNA in the liver and selected parameters of disease activity and liver damage. A group of 48 chronically HCV infected patients (7-63 years old, mean 39 years) was evaluated. In the patients we assessed the activity of transaminases (ALT, AST), gammaglutamyltransferase (GGTP), and alkaline phosphatase (ALP). The patients underwent routine liver biopsies and the liver tissue was examined histopathologically and in order to detect the presence of HCV-RNA, by means of a combined procedure joining a new method of HCV-RNA extraction from the liver tissue and HCV-RNA detection with RT-PCR automatic Cobas Amplicor Hepatitis C ver. 2.0 assay (Roche Diagnostics). At the time of the liver biopsy, 44 of the patients were identified as having detectable serum HCV-RNA (as examined by means of Cobas Amplicor Hepatitis C ver. 2.0 assay), 3 patients were negative, and 1 was not tested. The presence of HCV-RNA in the liver tissues was detected in 39 cases (81.2%). In the parameters examined we have not found any significant differences between currently liver HCV-RNA positive and negative patients. Presence of the detectable HCV-RNA in the liver bioptats from chronic hepatitis C patients does not correlate with disease activity or level of liver damage.     

Concordance in a World without a Gold Standard: A New Non-Invasive Methodology for Improving Accuracy of Fibrosis Markers

Background

Assessing liver fibrosis is traditionally performed by biopsy, an imperfect gold standard. Non-invasive techniques, liver stiffness measurements (LSM) and biomarkers [FibroTest® (FT)], are widely used in countries where they are available. The aim was to identify factors associated with LSM accuracy using FT as a non-invasive endpoint and vice versa.

Methods

The proof of concept was taken using the manufacturers recommendations for excluding patients at high risk of false negative/positive. The hypothesis was that the concordance between LSM and FT, would be improved by excluding high-risk patients. Thereafter, the impact of potential variability factors was assessed by the same methods. Liver biopsy and independent endpoints were used to validate the results.

Results

Applying manufacturers'' recommendations in 2,004 patients increased the strength of concordance between LSM and FT (P<0.00001). Among the 1,338 patients satisfying recommendations, the methodology identified a significant LSM operator effect (P = 0.001) and the following variability factors (all P<0.01), related to LSM: male gender, older age, and NAFLD as a cause of liver disease. Biopsy confirmed in 391 patients these results.

Conclusion

This study has validated the concept of using the strength of concordance between non-invasive estimates of liver fibrosis for the identification of factors associated with variability and precautions of use.     

Liver in Leprosy: Histological and Biochemical Findings

The histological findings and their correlation with biochemical functions of the liver in 240 leprosy patients are presented. In 21% with tuberculoid leprosy and in 62% with lepromatous leprosy leprous granulomata were found in the liver. A significant prevalence of granulomatous lesions in the liver among patients with tuberculoid and borderline-tuberculoid leprosy of less than one year''s duration suggests that bacillaemia occurs early in all forms of leprosy.There was a direct correlation between bacterial index and the presence of acid-fast bacilli in the liver. Of 50 patients with negative skin smears seven had acid-fast bacilli at liver biopsy. From none of these liver homogenates were acid-fast bacilli grown on culture in Löwenstein-Jensen medium.The alterations in liver functions were more consistently seen when acid-fast bacilli were associated with the presence of leprous granulomatous lesions. The acid-fast bacilli were found to persist even after one to five years of specific antileprosy therapy and after the bacilli in the skin had cleared up. This may explain the relatively frequent recrudescence or relapse of the bacillated types of leprosy when specific antileprosy therapy is stopped soon after bacterial negativity is attained on skin smears.     

Use of Non-Invasive Parameters of Non-Alcoholic Steatohepatitis and Liver Fibrosis in Daily Practice - An Exploratory Case-Control Study

Background

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of a metabolic syndrome. To date, liver biopsy has been the gold standard used to differentiate between simple steatosis and steatohepatitis/fibrosis. Our aim was to compare the relevance of serum non-invasive parameters and scoring systems in the staging of liver fibrosis and non-alcoholic steatohepatitis (NASH) in patients with NAFLD.

Methods and Findings

A total of 112 consecutive patients diagnosed with NAFLD were included. A liver biopsy was performed on 56 patients. The Kleiner score was used for the staging and grading of the histology. Non-invasive parameters for fibrosis (hyaluronic acid; AST/ALT; fibrosis scoring indexes OELF, ELF, BARD score, APRI, NAFLD fibrosis score); and inflammation (M30 and M65 cytokeratin-18 fragments) were measured and calculated. The same analyses were performed in 56 patients diagnosed with NAFLD, who were not indicated for liver biopsy. Based on the liver histology, NASH was diagnosed in 38 patients; simple steatosis in 18 patients. A cut-off value of 750 U/L of serum M65 discriminated patients with and without NASH with a 80% sensitivity and 82% specificity (95% CI:57–95). Fibrosis stage F0–F2 was present in 39 patients; F3–F4 in 17 patients. Serum concentrations of hyaluronic acid were higher in patients with advanced fibrosis (p<0.01); a cut-off value of 25 µg/l discriminated patients with F3–F4 with a 90% sensitivity and 84% specificity from those with F0–F2 (95% CI:59–99). When applying the non-invasive criteria to those patients without a liver biopsy, NASH could only be diagnosed in 16%; however, advanced fibrosis could be diagnosed in 35% of them.

Conclusions

In patients with NAFLD, non-invasive serum parameters with a high accuracy can differentiate those patients with NASH and/or advanced fibrosis from those with simple steatosis. A substantial portion of those patients not indicated for liver biopsy might have undiagnosed advanced fibrosis.     

NEEDLE BIOPSY OF THE LIVER—General Considerations

Needle biopsy of the liver provides concrete diagnostic information that cannot be as readily obtained in any other way. This report reviews 401 liver biopsies in 312 patients.The major indications for use of this procedure are: To determine the cause of an obscure liver enlargement; to establish the cause of jaundice; to distinguish between malignant disease and cirrhosis of the liver; to determine when hepatitis has subsided; and to evaluate the results of treatment. At times, systemic disease that has not been recognized by other means may be diagnosed by this technique. There is risk in performing this test, and the 0.25 per cent mortality in this series compares favorably with that reported from other clinics. Where the diagnosis by biopsy could be compared with observations at operation or autopsy, the correct diagnosis was made by biopsy in 85 per cent of cases. Greater accuracy was obtained by two or more biopsic examinations in one case then by single biopsy.In several cases in which surgical operation was considered, biopsic information made it unnecessary, and vice versa.     

Needle biopsy of the liver; general considerations

Needle biopsy of the liver provides concrete diagnostic information that cannot be as readily obtained in any other way. This report reviews 401 liver biopsies in 312 patients. THE MAJOR INDICATIONS FOR USE OF THIS PROCEDURE ARE: To determine the cause of an obscure liver enlargement; to establish the cause of jaundice; to distinguish between malignant disease and cirrhosis of the liver; to determine when hepatitis has subsided; and to evaluate the results of treatment. At times, systemic disease that has not been recognized by other means may be diagnosed by this technique. There is risk in performing this test, and the 0.25 per cent mortality in this series compares favorably with that reported from other clinics. Where the diagnosis by biopsy could be compared with observations at operation or autopsy, the correct diagnosis was made by biopsy in 85 per cent of cases. Greater accuracy was obtained by two or more biopsic examinations in one case then by single biopsy. In several cases in which surgical operation was considered, biopsic information made it unnecessary, and vice versa.     

Percutaneous fine-needle aspiration biopsy of intra-abdominal masses.

Percutaneous fine-needle aspiration biopsies were performed in 51 patients with various intra-abdominal masses localized by palpation, radiologic studies, ultrasonography or radioisotope scanning. Biopsy specimens were considered positive for malignant disease in 35 (85%) of the 41 patients with such disease, including 26 (96%) of the 27 with metastases. There was one false-positive diagnosis of malignant disease from the biopsy specimens. Surgery became unnecessary as a result of aspiration biopsy in at least 12 patients. One patient showed evidence of intrahepatic bleeding during liver biopsy but recovered spontaneously, and the liver appeared normal at laparotomy 3 weeks later. Aspiration biopsy is an accurate, relatively painless, inexpensive and safe method of establishing a diagnosis of intraabdominal malignant disease. Considerable experience of the cytologist is necessary for good results.     

Cost effectiveness of fibrosis assessment prior to treatment for chronic hepatitis C patients

Background and Aims

Chronic hepatitis C (HCV) is a liver disease affecting over 3 million Americans. Liver biopsy is the gold standard for assessing liver fibrosis and is used as a benchmark for initiating treatment, though it is expensive and carries risks of complications. FibroTest is a non-invasive biomarker assay for fibrosis, proposed as a screening alternative to biopsy.

Methods

We assessed the cost-effectiveness of FibroTest and liver biopsy used alone or sequentially for six strategies followed by treatment of eligible U.S. patients: FibroTest only; FibroTest with liver biopsy for ambiguous results; FibroTest followed by biopsy to rule in; or to rule out significant fibrosis; biopsy only (recommended practice); and treatment without screening. We developed a Markov model of chronic HCV that tracks fibrosis progression. Outcomes were expressed as expected lifetime costs (2009 USD), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICER).

Results

Treatment of chronic HCV without fibrosis screening is preferred for both men and women. For genotype 1 patients treated with pegylated interferon and ribavirin, the ICERs are $5,400/QALY (men) and $6,300/QALY (women) compared to FibroTest only; the ICERs increase to $27,200/QALY (men) and $30,000/QALY (women) with the addition of telaprevir. For genotypes 2 and 3, treatment is more effective and less costly than all alternatives. In clinical settings where testing is required prior to treatment, FibroTest only is more effective and less costly than liver biopsy. These results are robust to multi-way and probabilistic sensitivity analyses.

Conclusions

Early treatment of chronic HCV is superior to the other fibrosis screening strategies. In clinical settings where testing is required, FibroTest screening is a cost-effective alternative to liver biopsy.     

Partial hepatectomy of marmoset: clinical and pathological effects and utility in microsomal enzyme analysis.

Liver biopsy based on a partial hepatectomy technique (shearing) was performed in 10 common marmosets (Callithrix jacchus). This is a preliminary study to evaluate the effects of drugs on hepatic microsomal enzymes: cytochrome P-450 and T4 uridine diphosphate glucuronyl transferase (T4-UDPGT), by comparing post-treatment values with pre-treatment values individually with a limited number of animals. The effects of the biopsy on clinical findings and liver pathology were evaluated during the first 5 post-surgical weeks. Although the plasma aspartate aminotransferase (AST) activities tended to decrease from 1 to 4 weeks post-surgery, no abnormality was noted in clinical sign, body weight, the hematocrit value or other blood chemical values. At necropsy, adhesion of the sheared site of the liver to the parietal peritoneum or the small intestine was evident in 2 of the 4 marmosets. Microscopic examination revealed focal fibrosis in the liver, but it was localized around the sheared site. Based on the above results, it was concluded that liver biopsy must be performed more than one month before administration of the drug to be tested. The biopsy samples and the whole liver samples obtained at autopsy were subjected to analysis of microsomal protein content, cytochrome P-450 content and T4-UDPGT activity. In comparison with the values from the whole liver samples, those from the biopsy samples showed no significant difference. Furthermore, there was a significant correlation rather than difference between matched values. This suggested that partial hepatectomy is a useful method for obtaining pretreatment values in liver biochemistry to evaluate the effects of drug-treatment in individual animals.