A comparison of 31P magnetic resonance spectroscopy and microbubble-enhanced ultrasound for characterizing hepatitis c-related liver disease.

We compared in vivo hepatic (31) P magnetic resonance spectroscopy ((31) P MRS) and hepatic vein transit times (HVTT) using contrast-enhanced ultrasound with a microbubble agent to assess the severity of hepatitis C virus (HCV)-related liver disease. Forty-six patients with biopsy-proven HCV-related liver disease and nine healthy volunteers had (31) P MRS and HVTT performed on the same day. (31) P MR spectra were obtained at 1.5 T. Peak areas were calculated for metabolites, including phosphomonoesters (PME) and phosphodiesters (PDE). Patients also had the microbubble ultrasound contrast agent, Levovist (2 g), injected into an antecubital vein, and time-intensity Doppler ultrasound signals of the right and middle hepatic veins were measured. The HVTT was calculated as the time from injection to a sustained rise in Doppler signal 10% greater than baseline. The shortest times were used for analysis. Based on Ishak histological scoring, there were 15 patients with mild hepatitis, 20 with moderate/severe hepatitis and 11 with cirrhosis. With increasing severity of disease, the PME/PDE ratio was steadily elevated, while the HVTT showed a monotonic decrease. Both imaging modalities could separate patients with cirrhosis from the mild and moderate/severe hepatitis groups. No statistical difference was observed in the accuracy of each test to denote mild, moderate/severe hepatitis and cirrhosis (Fisher's exact test P =1.00). (31) P MRS and HVTT show much promise as noninvasive imaging tests for assessing the severity of chronic liver disease. Both are equally effective and highly sensitive in detecting cirrhosis.

Hepatic vein transit times of a microbubble agent in assessing response to antiviral treatment in patients with chronic hepatitis C.

Microbubble measurement of hepatic vein transit times (HVTT) may have the potential to assess severity of hepatitis C virus (HCV)-related liver disease, where there is a shorter HVTT with more severe disease. We investigated the utility of this test as a marker of response to antiviral treatment. Thirty-seven patients with biopsy-proven HCV-related disease undergoing antiviral treatment were studied. All had baseline scans and then repeat scans 6 months after the end of treatment. HVTT using Levovist were obtained from the right and middle hepatic veins, and the shorter time was used for analysis. The aspartate aminotransferase to platelet ratio index (APRI) scores were calculated retrospectively. There were seven patients with mild hepatitis, 23 with moderate/severe hepatitis and seven with cirrhosis. The mean baseline HVTT in responders ± SE increased from 27.3 ± 2.29 s to 33.5 ± 2.8 s posttreatment (P = 0.01). In the 10 nonresponders, the HVTT remained the same; 43.3 ± 9 s baseline compared to 44 ± 7.8 s posttreatment (P = 0.84). This trend was also seen with the APRI score where in responders, the mean score decreased from 1.1 ± 0.2 to 0.74 ± 1 (P = 0.03) and in nonresponders, the score remained unchanged; 0.88 ± 0.2 compared to 0.84 ± 0.2 (P = 0.31). HVTT measurement lengthened, while APRI scores decreased in patients who responded to antiviral treatment while both remained the same, shortened (HVTT) or increased (APRI), respectively, in patients who were nonresponders. These results are encouraging and indicate that these tests could be potentially used as markers of response to treatment and could obviate the need for serial biopsies in antiviral future treatment studies.

Optimal combinations of ultrasound-based and serum markers of disease severity in patients with chronic hepatitis C.

Combinations of noninvasive markers may improve discrimination of chronic liver disease severity. The aims of this study were to compare four validated serum and ultrasound-based markers of hepatic disease severity head-to-head with liver biopsy and to assess optimal combinations with consideration of cost. A total of 67 patients with biopsy-proven chronic hepatitis C underwent all four techniques on the same visit [aspartate aminotransferase (AST) to platelet ratio index (APRI); Enhanced Liver Fibrosis (ELF) panel; transient elastography (TE) and ultrasound microbubble hepatic transit times (HTT)]. Markers were combined according to increasing financial cost and ordinal regression used to determine contributions. APRI, ELF, TE and HTT predicted cirrhosis with diagnostic accuracy of 86%, 91%, 90% and 83% respectively. ELF and TE were the most reliable tests with an intra-class correlation of 0.94 each. Either ELF or TE significantly enhanced the prediction of fibrosis stage when combined with APRI, but when combined together, did not improve the model further. Addition of third or fourth markers did not significantly improve prediction of fibrosis. Combination of APRI with either ELF or TE effectively predicts fibrosis stage, but combinations of three or more tests lead to redundancy of information and increased cost.

A missense mutation in the non-neural G-protein alpha-subunit isoforms modulates susceptibility to obesity.

OBJECTIVE: The Gnas transcription unit located within an imprinting region encodes several proteins, including the G-protein alpha-subunit, Gsalpha, its isoform XLalphas and their variant truncated neural forms GsalphaN1 and XLN1. Gsalpha and GsalphaN1 are expressed predominantly from the maternally derived allele in some tissues, whereas XLalphas and XLN1 are expressed exclusively from the paternally derived allele. The relative contribution of full-length Gsalpha and XLalphas, and truncated forms GsalphaN1 and XLN1 to phenotype is unknown. The edematous-small point mutation (Oed-Sml) in exon 6 of Gnas lies downstream of GsalphaN1 and XLN1, but affects full-length Gsalpha and XLalphas, allowing us to address the role of full-length Gsalpha and XLalphas. The aim of this study was therefore to determine the metabolic phenotypes of Oed and Sml mice, and to correlate phenotypes with affected transcripts. METHODS: Mice were fed standard or high-fat diets and weighed regularly. Fat mass was determined by DEXA analysis. Indirect calorimetry was used to measure metabolic rate. Glucose was measured in tolerance tests and biochemical parameters in fasted plasma samples. Histological analysis of fat and liver was carried out post mortem. RESULTS: Oed mice are obese on either diet and have a reduced metabolic rate. Sml mice are lean and are resistant to a high-fat diet and have an increased metabolic rate. CONCLUSION: Adult Oed and Sml mice have opposite metabolic phenotypes. On maternal inheritance, the obese Oed phenotype can be attributed to non-functional full-length Gsalpha. In contrast, on paternal inheritance, Sml mice were small and resistant to the development of obesity on a high-fat diet, effects that can be attributed to mutant XLalphas. Thus, the neural isoforms, GsalphaN1 and XLN1, do not appear to play a role in these metabolic phenotypes.

Characterization of materials eliciting foreign body reaction in stapled human gastrointestinal anastomoses.

BACKGROUND: Staples are made of titanium, which elicits minimal tissue reaction. The authors have encountered foreign body reaction associated with stapled human gastrointestinal anastomoses, although the literature has no reports of this. The aim of this study was to identify the refractile foreign materials causing this reaction. METHODS: Histological sections were taken from 14 gastrointestinal specimens from patients with a history of a stapled anastomosis within the specimen excised. These were reviewed by light and polarization microscopy. Scanning electron microscopy and energy dispersive X-ray analysis were carried out on these sections, staples and stapler cartridges used for gastrointestinal surgery. RESULTS: Foreign bodies rich in fluorine were found in three patients, and those rich in carbon in 12. Other elements identified included oxygen, calcium, sodium, potassium, magnesium, aluminium and silicon. One specimen was found to contain titanium with no surrounding foreign body reaction. Stapler cartridges contained carbon, oxygen, fluorine, calcium, sodium, potassium, magnesium, aluminium, silicon and traces of titanium. Staples were composed of pure titanium with some fibrous material on the surface containing elements found in stapler cartridges. CONCLUSION: The presence of foreign body reaction was confirmed in stapled human gastrointestinal anastomoses. The source of refractile materials eliciting this reaction was the stapler cartridges.

Case 31: Eosinophilia and pruritus.

A 39-year-old man presented with a pruritic rash, abdominal pain, weight loss and eosinophilia. A subsequent emergency laparotomy disclosed the nature of his underlying illness and the cause of the eosinophilia.

Liver changes associated with cholecystitis.

AIMS: To investigate the histopathological changes in the livers of patients undergoing cholecystectomy and to relate these changes to the underlying biliary tract pathology. METHODS: Liver changes in 67 patients undergoing cholecystectomy were investigated. Sixty three had gall stones, one cholesterolosis only, and there were three cases of acute acalculous cholecystitis. RESULTS: Only 34% of the patients had completely normal liver biopsy specimens. The most clinically important pathology was found in 11 of the 14 patients with choledocholithiasis: three of these had cholangitis and eight had features of large bile duct obstruction (four also had chronic cholestasis and portal-portal linking fibrosis). Non-specific reactive hepatitis was the most common abnormality in the remaining 53 patients with cholecystitis alone, and was found in 18. A further four patients had chronic cholestasis without fibrosis and early primary biliary cirrhosis was a coincidental finding in another. Clinical symptoms were poorly correlated with gall bladder and liver pathology apart from an association between jaundice and choledocholithiasis. Liver function tests of obstructive pattern were noted in 23 of 58 patients, most of whom had choledocholithiasis or non-specific reactive hepatitis. Bile cultures were positive in 10 of 42 patients, predominantly in cases of cholangitis and acute cholecystitis. CONCLUSIONS: Cholangitis and extensive fibrosis associated with large bile duct obstruction are common findings in patients with choledocholithiasis. The liver disease may progress to secondary biliary cirrhosis if the obstruction is not relieved, emphasising the need for early surgery. A peroperative liver biopsy may be useful to exclude cirrhosis in these patients, but is unlikely to be informative in those with cholecystitis alone.

IgA deposition in alcoholic liver disease.

Immunoglobulin deposition in alcoholic and non-alcoholic liver disease was studied using an indirect immunoperoxidase technique. A continuous pattern of IgA deposition, with IgA outlining the sinusoids, was shown to be a specific and sensitive marker for liver disease caused by alcohol in both cirrhotic and non-cirrhotic livers. The sensitivity was lowest in cases of alcoholic disease showing fatty change alone. In one case it was possible to show the absence of IgA in liver disease caused by a drug, which was histologically indistinguishable from alcoholic hepatitis.

A sebaceous cyst with a difference: Dermatobia hominis.

Dermatobia hominis causes furuncular myiasis and is endemic to South America. This report describes a case in a young woman who had recently visited Belize, highlighting the importance of clinical history (including travel history) and close liaison between pathologist and surgeon.

Iron overload in multiply transfused patients who are HIV seropositive.

AIMS: To assess histologically the amount of iron deposited in liver biopsy specimens from HIV positive patients; and to perform estimations of liver iron on tissue from patients with an increase in parenchymal stainable iron. To correlate the amount of blood transfused and the degree of iron overload. METHODS: Liver biopsy specimens (n = 120) from 109 HIV positive patients, 74 of whom had AIDS, were examined retrospectively and the amount of iron, as visualised with Perls's stain, was graded. Fibrosis was assessed using connective tissue stains. Estimations of liver iron were performed on tissue retrieved from paraffin wax blocks in cases with histological grade 3 or 4 iron overload. The amount of blood transfused before liver biopsy was determined from the notes for each patient. RESULTS: Fifteen of the 120 liver biopsy specimens had significantly increased amounts of iron in their hepatocytes, as assessed histologically, and this was confirmed in seven cases by measurement of liver iron. There was a close correlation between the amount of blood transfused and the degree of iron overload. In the initial biopsy specimens only one case showed portal tract expansion. Three of the five patients who had repeat biopsies, however, showed progressive fibrosis. CONCLUSION: Multiply transfused HIV positive patients may develop clinically important iron overload and are at risk of developing progressive fibrosis. Superimposed liver disease, especially viral hepatitis, in these high risk patients may exacerbate the effects of the iron overload.

Increase in alcohol related deaths: is hepatitis C a factor?

AIM: To evaluate recent trends in alcohol related deaths in the UK and to consider possible causative factors. DESIGN: Observational retrospective study of the database of the Office for National Statistics, alcohol consumption data reported by the General Household Survey, and other published data. SETTING: England, 1993-9. RESULTS: Deaths for each million of the population from alcohol related illness increased by 59% in men and 40% in women over the years 1993 to 1999. One subgroup of alcohol related deaths, ICD 571.3 (alcoholic liver damage unspecified), showed a 243% increase in men aged 40 to 49 years over the same period. Figures for younger men, and women in all age groups, showed less pronounced increases. There has been no associated rise in alcohol intake. There has been an increase in the incidence of hepatitis C virus (HCV) infection in recent years, and alcohol consumption in HCV positive individuals accelerates the progression to cirrhosis. Circumstantial evidence links the rise in HCV infection to the use of illicit drugs in the 1970s and 1980s, among those currently aged 40 to 59 years. CONCLUSIONS: The recent increase in alcohol related deaths cannot be solely explained by a change in drinking habits. It is suggested that this probably results from the rapid progression of alcoholic cirrhosis in people who have acquired HCV infection through intravenous drug use. Alcohol consumption in HCV positive individuals is firmly linked with a poor outcome.

A solitary benign lymphoid polyp of the rectum in a 51 year old woman.

A 51 year old woman presented with rectal bleeding from a mass lying just above the dentate line. Multiple biopsies were taken before the diagnosis of a benign lymphoid polyp was made. This is a rare condition that more commonly presents in children and poses a diagnostic challenge.

Hepatitis C and bile duct loss.

AIM: To assess whether bile duct loss is associated with the bile duct damage induced by chronic hepatitis C. METHODS: Sections were examined from 171 liver biopsy specimens from patients with chronic hepatitis C, 98 biopsy specimens from patients with chronic hepatitis B, 25 postmortem specimens from patients with no evidence of liver disease, and 23 patients who underwent protocol liver biopsy at the time of cholecystectomy. RESULTS: The bile duct:portal tract ratio for the hepatitis C group was 0.89, for the hepatitis B group was 0.93 and for the two control groups was 0.96 and 0.90, respectively. The ratio was lower in the hepatitis C group than in the other three. In no case of chronic hepatitis C was the ratio less than 0.60. In the hepatitis C group greater bile duct loss was seen in cirrhotic patients. CONCLUSIONS: Hepatitis C is associated with bile duct loss and this was related to the stage of the disease. However, in the cases studied this did not reach what is generally considered to be significant (that is, greater than 50% of portal tracts lacking bile ducts). This does not preclude a contributory effect of hepatitis C to bile duct loss in the presence of other risk factors, especially in liver transplant recipients.

Biopsy pathology of acquired immune deficiency syndrome (AIDS).

Between January 1982 and May 1986 279 biopsy specimens from 82 patients with acquired immune deficiency syndrome (AIDS) were examined. A wide variety of infectious conditions were diagnosed, the commonest being Pneumocystis pneumonia (n = 36), cytomegalovirus (n = 21), a variety of fungi (n = 8), mycobacteria (n = 7). Kaposi's sarcoma was the commonest tumour (n = 40), and there were two cases of extranodal lymphoma. Striking features were the unusual sites of disease and the occasional paucity of organisms.

Diagnosis of lung disease in acquired immune deficiency syndrome: biopsy or cytology and implications for management.

One hundred and twenty consecutive bronchoscopic examinations were carried out on 80 patients with acquired immune deficiency syndrome (AIDS) between January 1982 and December 1986. Ninety one paired biopsy and cytology specimens from 72 of these patients were analysed. There was no significant difference between biopsy and cytology in diagnosing Pneumocystis carinii pneumonia (0.95 greater than p greater than 0.1). In 10 cases P carinii pneumonia was diagnosed by biopsy but not cytology and in seven cases by cytology but not biopsy. Nineteen patients had multiple infections or Kaposi's sarcoma. Biopsy was more useful than cytology in the diagnosis of other infections (n = 20) and Kaposi's sarcoma (n = 2) with positive cytological correlation in only three of the infections. Biopsy and cytology together have a diagnostic yield of 78.3%. We conclude that all patients presenting with respiratory disease who have, or are in a high risk group for, AIDS should be examined by bronchoscopy at an early stage with both cytology and biopsy.

Histological and immunohistochemical study of hepatitis B virus in human immunodeficiency virus infection.

Because the risk factors for human immunodeficiency virus (HIV) infection and hepatitis B (HBV) are similar and therefore coinfection is not uncommon, a detailed histological and immunohistochemical study of chronic hepatitis B infection in a group of 20 HIV positive Caucasian males (who did not have AIDS) and 30 HIV negative controls were undertaken. Using both the conventional histological classification and the Knodell histological activity index it was shown that HIV negative patients were more likely to have active disease and also more scarring than HIV positive patients. Hepatitis B surface antigen (HBsAg) expression was not significantly different between the two groups but expression of hepatitis Be antigen (HBeAg) and HBV-DNA polymerase was greater in those who were HIV positive. HIV positive patients are therefore more likely to have immunohistochemical markers of active viral replication, although histologically, liver disease is less severe. These findings have important implications for assessing the biopsy specimens in this group of patients and for treatment strategies aimed at improving their immune function.

Disseminated pneumocystis carinii infection in AIDS.

Eight patients with AIDS and Pneumocystis carinii infection were studied. Protean manifestations were a feature not untypical of disseminated pneumocystosis. Aerosolised pentamidine as prophylaxis against P carinii pneumonia was ineffective at suppressing dissemination. The knowledge that extrapulmonary infection can occur has implications for the detection and treatment of, and prophylaxis against, P carinii infection. The survival of patients with disseminated pneumocystosis is particularly poor, and may be due to a lack of clinical awareness and consequent delay in diagnosis.

Placental pathology, antiphospholipid antibodies, and pregnancy outcome in recurrent miscarriage patients.

OBJECTIVE: To examine whether there are characteristic histological features in placentas from ongoing pregnancies of patients with a history of recurrent miscarriage, with and without primary antiphospholipid antibody syndrome, in relation to clinical pregnancy outcome. METHODS: Patients attending a recurrent miscarriage clinic were investigated and treated according to an established protocol. One hundred twenty-one consecutive patients achieving a potentially viable pregnancy (at least 24 completed weeks' gestation), including 60 primary antiphospholipid antibody syndrome-positive cases and 61 primary antiphospholipid antibody syndrome-negative cases were included. After delivery, placental pathologic examination was carried out by a pathologist unaware of the clinical details. Histological sections were examined by two pathologists independently. Pregnancy outcome and placental findings were reviewed in relation to the maternal antiphospholipid antibody status. RESULTS: Pregnancy outcome was similar in primary antiphospholipid antibody syndrome-positive and primary antiphospholipid antibody syndrome-negative groups regarding gestation at delivery and antepartum obstetric complications. Several histological placental abnormalities were identified in both groups, but most pregnancies were clinically uncomplicated, with no significant placental abnormalities. In cases with pregnancy complications, the placental pathology was primarily that of uteroplacental vasculopathy, such as placental infarction and preeclampsia, but there were no specific placental lesions or patterns of abnormalities characteristic of primary antiphospholipid antibody syndrome-positive patients. A small subgroup of primary antiphospholipid antibody syndrome-positive patients may be at increased risk of development of maternal floor infarction or massive perivillus fibrin deposition. CONCLUSION: There are no specific histopathologic placental abnormalities characteristic of treated patients with antiphospholipid antibody syndrome and poor reproductive history, but complications of uteroplacental disease are more common.

Is the relationship between angiogenesis and metastasis in breast cancer real?

The suggested link between angiogenesis in breast cancer and metastasis remains unsubstantiated. We tested this relationship in primary breast carcinomas from 37 patients with a median follow-up 9.5 years (Cohort 1) and 50 patients with a median follow-up of 1.5 years (Cohort 2). Angiogenesis was assessed by counting vessel density after immunohistochemical staining of vascular endothelium for factor VIII. Patients were grouped according to whether metastasis (defined as spread to axillary lymph nodes, distant sites or both) had occurred. The mean +/- SD scores in Cohort 1 when metastasis was absent and present, respectively, were 15.6 +/- 4.9 (n = 21) and 14.1 +/- 3.7 (n = 16). In Cohort 2 the scores were 15.4 +/- 5.8 (n = 26) and 14.5 +/- 4.9 (n = 24). There was no significant difference between these scores in either cohort. Multivariate analysis demonstrated lymph node involvement (P < 0.001) and tumour size (P < 0.001) but not angiogenesis score (P > 0.05) to predict distant metastasis. This evidence argues against any prognostic significance of angiogenesis in breast carcinoma.

Serum F protein: a new sensitive and specific test of hepatocellular damage.

F protein is a 44-kDa protein which is found mostly in the liver and circulates at much lower concentrations in the serum. Serum F protein has been measured, using a recently developed radioimmunoassay, in a variety of diseases and was appreciably raised only in patients with hepatocellular damage. The serum F protein concentration was a more sensitive and specific marker of liver damage than conventional liver function tests and showed a close correlation with the histological assessment of liver damage (r = 0.86, P less than 0.001). This new marker may be of value in the diagnosis and treatment of liver disease.