Enrique G. Molina

Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection

OBJECTIVES:Needle liver biopsy has been shown to have a high rate of sampling error in patients with diffuse parenchymal liver diseases. In these cases, the sample of liver tissue does not reflect the true degree of inflammation, fibrosis, or cirrhosis, despite an adequate sample size. The aim of this study was to determine the rate and extent of sampling error in patients with chronic hepatitis C virus infection, and to assess the intraobserver variation with the commonly used scoring system proposed by Scheuer and modified by Batts and Ludwig.METHODS:A total of 124 patients with chronic hepatitis C virus infection underwent simultaneous laparoscopy-guided biopsies of the right and left hepatic lobes. Formalin-fixed paraffin-embedded sections were stained with hematoxylin and eosin and with trichrome. The slides were blindly coded and randomly divided among two hepatopathologists. Inflammation and fibrosis were scored according to the standard grading (inflammation) and staging (fibrosis) method based on the modified Scheuer system. Following the interpretation, the slides were uncoded to compare the results of the right and left lobes. Fifty of the samples were blindly resubmitted to each of the pathologists to determine the intraobserver variation.RESULTS:Thirty of 124 patients (24.2%) had a difference of at least one grade, and 41 of 124 patients (33.1%) had a difference of at least one stage between the right and left lobes. In 18 patients (14.5%), interpretation of cirrhosis was given in one lobe, whereas stage 3 fibrosis was given in the other. A difference of two stages or two grades was found in only three (2.4%) and two (1.6%) patients, respectively. Of the 50 samples that were examined twice, the grading by each pathologist on the second examination differed from the first examination in 0% and 4%, and the staging differed in 6% and 10%, respectively. All observed variations were of one grade or one stage.CONCLUSIONS:Liver biopsy samples taken from the right and left hepatic lobes differed in histological grading and staging in a large proportion of chronic hepatitis C virus patients; however, differences of more than one stage or grade were uncommon. A sampling error may have led to underdiagnosis of cirrhosis in 14.5% of the patients. These differences could not be attributed to intraobserver variation, which appeared to be low.

Reliability of histopathologic assessment for the differentiation of recurrent hepatitis C from acute rejection after liver transplantation

Histopathologic assessment is considered essential for the differentiation of recurrent hepatitis C (RHC) from acute cellular rejection (ACR) after liver transplantation (LT); however, there is limited information regarding its reliability. The aim of this study was to determine the interobserver and intraobserver agreement of the histopathologic diagnosis of RHC vs. ACR, and to determine the reliability of specific histopathologic features for the differentiation of RHC from ACR. Liver biopsy specimens from 105 consecutive patients transplanted for hepatitis C virus (HCV)‐related liver disease were studied retrospectively. All the biopsies were performed for evaluation of abnormal liver enzymes within the 1st year after LT. The slides were blindly coded and assessed by 5 liver‐transplant pathologists, practicing at 3 medical centers. The pathologists were asked to render a diagnosis, and determine the severity of the disease. Four of the pathologists were asked to determine the presence and severity of 36 histopathologic features. A total of 34 of the samples were then blindly resubmitted to each of the 4 pathologists to determine the intraobserver agreement. There was a slight agreement (κ = .12) among the 5 pathologists on the histopathologic diagnosis. All 5 pathologists were in agreement on the diagnosis of RHC in only 5 patients (5%) and on the diagnosis of ACR in only 2 patients (2%). The best agreement among any 4 pathologists was fair (κ = .20). Slight to moderate agreement occurred on the main histological features considered to be important in the diagnosis of ACR. Intraobserver agreement ranged from slight (κ = .19) to moderate (κ = .42) among 4 pathologists. In conclusion, the histopathologic differentiation of RHC from ACR after LT had relatively low interobserver and intraobserver agreement rates, and hence showed low reliability. Histopathologic assessment should be used cautiously for the differentiation of RHC from ACR post‐LT. (Liver Transpl 2004;10:1233–1239.)

Large cystic lesions of the liver in adults: a 15-year experience in a tertiary center

BACKGROUND Cystic lesions of the liver consist of a heterogeneous group of disorders and may present a diagnostic and therapeutic challenge. Large hepatic cysts tend to be symptomatic and can cause complications more often than smaller ones. STUDY DESIGN We performed a retrospective review of adults diagnosed with large (> or = 4 cm) hepatic cystic lesions at our center, over a period of 15 years. Polycystic disease and abscesses were not included. RESULTS Seventy-eight patients were identified. In 57 the lesions were simple cysts, in 8 echinococcal cysts, in 8 hepatobiliary cystadenomas, and in 1 hepatobiliary cystadenocarcinoma. In four patients, the precise diagnosis could not be ascertained. Mean size was 12.1 cm (range, 4 to 30 cm). Most simple cysts were found in women (F:M, 49:8). Bleeding into a cyst (two patients) and infection (one patient) were rare manifestations. Percutaneous aspiration of 28 simple cysts resulted in recurrence in 100% of the cases within 3 weeks to 9 months (mean 4(1/2) months). Forty-eight patients were treated surgically by wide unroofing or resection (laparoscopically in 18), which resulted in low recurrence rates (11% for laparoscopy and 13% for open unroofing). Four of the eight patients with echinococcal cysts were symptomatic. All were treated by open resection after irrigation of the cavity with hypertonic saline. There was no recurrence during a followup period of 2 to 14 years. Hepatobiliary cystadenomas occurred more commonly in women (F:M, 7:1) and in the left hepatic lobe (left:right, 8:0). Seven were multiloculated. All were treated by open resection, with no recurrence, and none had malignant changes. Cystadenocarcinoma was diagnosed in a 77-year-old man, and was treated by left hepatic lobectomy. CONCLUSIONS Large symptomatic simple cysts invariably recur after percutaneous aspiration. Laparoscopic unroofing can be successfully undertaken, with a low recurrence rate. Open resection after irrigation with hypertonic saline is a safe and effective treatment for echinococcal cysts. Hepatobiliary cystadenomas have predilection for women and for the left hepatic lobe. Malignant transformation is an uncommon but real risk. Open resection is a safe and effective treatment for hepatobiliary cystadenoma, and is associated with a low recurrence rate.

Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease

Pruritus due to cholestatic liver disease can be particularly difficult to manage and frequently is intractable to a variety of medical therapies. The aim of our study is to evaluate the efficacy of Δ-9-tetrahydrocannabinol (Δ-9-THC) for intractable cholestatic related pruritus (ICRP) that has failed conventional (and unconventional) remedies. Three patients were evaluated for plasmapheresis because of ICRP. All 3 patients had previously been extensively treated with standard therapies for ICRP including: diphenhydramine, chlorpheniramine, cholestyramine, rifampicin, phenobarbital, doxepin, naltrexone, UV therapy, and topical lotions. Even multiple courses of plasmapheresis were performed without any benefit for the intractable pruritus. All patients reported significant decreases in their quality of life, including lack of sleep, depression, inability to work, and suicidal ideations. All patients were started on 5 mg of Δ-9-THC (Marinol) at bedtime. All 3 patients reported a decrease in pruritus, marked improvement in sleep, and eventually were able to return to work. Resolution of depression occurred in two of three. Side effects related to the drug include one patient experiencing a disturbance in coordination. Marinol dosage was decreased to 2.5 mg in this patient with resolution of symptoms. The duration of antipruritic effect is approximately 4–6 hrs in all three patients suggesting the need for more frequent dosing. Δ-9-tetrahydrocannabinol may be an effective alternative in patients with intractable cholestatic pruritus.

Clinical manifestations of primary hepatic angiosarcoma.

Malignant tumors of the liver stemming from mesenchymal origins are rare neoplasms, <1% of primary malignant hepatic lesions. Primary hepatic angiosarcoma (PHA) is the most common (36%). This study describes the incidence and clinical characteristics of this rare tumor in two medical centers, over the past 18 years. We reviewed tumor registry files at Jackson Memorial Hospital and oncology data records at Cedars Medical Center, 1979–1997. A total of 865 primary hepatic tumors were identified, of which five cases (0.58%) were PHA; four were men, and the median age was 53 years. Symptoms and signs included: pain, anemia, fever of unknown origin, weight loss, abdominal mass, and hemoperitoneum. Median survival was only 6 months. In conclusion, primary hepatic angiosarcomas frequently are symptomatic. The presentation and preexisting factors are valuable in establishing a clinical suspicion to diagnose this rare tumor. Although imaging studies are helpful, they are not conclusive, and liver biopsy is usually required.

Experience with staging laparoscopy in pancreatic malignancy

BACKGROUND The role of diagnostic laparoscopy in the staging of abdominal malignancies is not well defined. METHODS We retrospectively reviewed the usefulness of diagnostic laparoscopy as a staging procedure in pancreatic malignancy. This experience between February 1988 and May 1997 involves 109 cases of suspected or proven pancreatic malignancy. All laparoscopies were performed with the patient under conscious sedation and local anesthesia in an endoscopy suite. RESULTS Of the 109 patients with pancreatic cancer, 45 (42%) had metastatic disease. The use of computed tomography (CT) alone revealed the existence of liver metastases in 10 of 109 (9%) patients, which were confirmed laparoscopically. The further use of laparoscopy identified metastases in 29 more cases: hepatic, 23; hepatic and peritoneal, 3; peritoneal and mesenteric, 1; and mesenteric, 2. CT in conjunction with laparoscopy therefore revealed metastatic liver, peritoneal, or mesenteric lesions in 39 of 109 (36%) patients with pancreatic cancer. After staging laparoscopy, 67 of 69 patients underwent laparotomy. Metastatic disease was identified at laparotomy in 6 more patients; however, only 4 of these patients had metastases to the liver whereas 2 had metastases to the peripancreatic lymph nodes. Therefore, in patients with pancreatic malignancy, the negative predictive value for the diagnosis of metastases to the liver, peritoneum or mesentery was 94% (61 of 65 patients). The positive predictive value of laparoscopy alone for the detection of metastatic disease to the liver, peritoneum, or mesentery was 88% (29 of 33 patients). Laparoscopy was successfully performed without complications in all patients with pancreatic cancer; however, one had a technically unsatisfactory examination. The overall rate of resectability after staging by imaging studies and laparoscopy was 57% (35 of 61 patients). CONCLUSIONS In patients with a negative CT for metastases, laparoscopic identification of metastases avoided unnecessary laparotomy in 29 of 99 (29%) patients with pancreatic cancer. Staging laparoscopy is indicated in all cases of pancreatic malignancy before an attempt at a surgical cure.

Does the heterozygous state of alpha-1 antitrypsin deficiency have a role in chronic liver diseases? Interim results of a large case-control study.

Background: The role of the heterozygous PiZ state of alpha-1 antitrypsin deficiency (&agr;1ATD) in the pathogenesis of chronic liver disease (LD) is still a matter of controversy. Aim: To determine the prevalence of &agr;1ATD heterozygote states in a large population of patients with established LD compared with individuals with no LD, and to determine whether the prevalence of PiZ is increased in patients with more severe LD. Methods: A cross sectional case-control study among patients with and without LD. Blood samples were tested for &agr;1AT levels and &agr;1AT phenotype. The severity of LD was determined by clinical evaluation, lab tests, imaging studies and histopathology. Results: In total, 1405 patients were enrolled; 651 with, and 754 without LD. Out of them, 173 patients had decompensated cirrhosis requiring liver transplantation. PiMZ was significantly more prevalent in White patients (3.5%) compared with Hispanics (1.7%; P = 0.029). There was no difference in PiMZ prevalence between the total LD group and the group with no LD (2.1% vs. 1.7%; P = 0.64). Within the LD group, 5.7% of 173 patients with decompensated LD, listed for liver transplantation, had PiMZ, compared with 2.1% of 478 patients with less severe LD (P = 0.016). Similarly, there was a disproportionately higher prevalence of PiZ among hepatitis C virus (HCV) patients (5.6%) and patients with nonalcoholic fatty liver disease (NAFLD) (5.0%) with decompensated LD, compared with HCV patients (1.2%) and NAFLD patients (1.9%) with less severe LD (P = 0.044 and 0.017, respectively). Patients with cryptogenic cirrhosis, who were not considered NAFLD patients, did not have a higher prevalence of PiMZ compared with patients with LD of known etiologies (1.9% vs. 2.3%; P = 0.12). Conclusions: We found no association between the heterozygous PiZ state of &agr;1ATD and the presence of chronic LD in-general or the presence of cryptogenic cirrhosis. In contrast, patients with decompensated LD of any etiology had a significantly higher prevalence of PiMZ compared with patients with compensated LD. Furthermore, in patients with chronic LD due to HCV or NAFLD there was a significant association between the PiMZ heterozygous state and increased severity of LD and the need for liver transplantation. These interim results suggest that the PiMZ &agr;1ATD heterozygous state may have a role in worsening LD due to HCV or NAFLD.

Successful living related liver transplantation in an adult with fulminant hepatic failure

We report a case of an adult female who developed fulminant hepatic failure (FHF) during the second trimester of pregnancy and underwent a successful living related liver transplantation because no cadaveric donor was available during the development of life-threatening symptoms. A left lateral segment hepatic graft was procured from her brother, whose body weight was similar to hers. Her postoperative course was complicated by bleeding at the biliary anastomosis and subsequently by a biliary leak. Nevertheless, the complications were corrected surgically and the patient recovered well with a good quality of life 5 months after the transplant. This case suggests that living related liver transplantation should be considered more frequently for adult FHF patients. As the window of therapeutic opportunity is narrow for the dramatic condition of FHF, wide acceptance of this procedure will be of great benefit for the patients suffering from FHF.

Liver enzymes elevation after HAART in HIV‐HCV co‐infection

Summary.  Hepatitis C virus (HCV) co‐infection is common among human immunodeficiency virus (HIV) patients. The incidence and risk factors associated with hepatotoxicity in this population after high active antiretroviral therapy (HAART) is initiated are still not well‐understood. We argued to evaluate the incidence and risk factors associated with liver enzyme elevation (LEE) and their clinical significance. A retrospective chart review of patients who started HAART and had follow up at our centre for at least 1 year was undertaken. The frequency and severity of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation after treatment initiation were investigated and searched for clinical manifestations.

Predictors of Cirrhosis in Hispanic Patients with Nonalcoholic Steatohepatitis

It is estimated that 43% of patients with nonalcoholic steatohepatitis (NASH) will progress to liver fibrosis or cirrhosis. Although NASH is more common in Hispanics, most studies have been conducted on Caucasians, and there is scarce information regarding ethnic differences in this disease. The aim of this study was to identify the independent predictors of cirrhosis in Hispanic patients with NASH. A retrospective case-control study was conducted on 80 patients with biopsy-proven NASH. Forty-two were Hispanic (study group) and 38 were Caucasians controlled for age and BMI (control group). Clinical, biochemical, and histologic features were analyzed for correlation with cirrhosis. There were no significant differences in demographic features between the two groups. In multivariate analysis, independent predictors of cirrhosis among Hispanic patients were age (OR, 1.07; 95% CI, 1.01–1.14) and AST/ALT ratio (OR, 10.56; 95% CI; 2.46–45.29), while independent predictors among non-Hispanic patients were age (OR, 1.085; 95% CI, 1.0–1.186), and diabetes mellitus (OR, 6.46; 95% CI, 1.19–35.07). In patients with NASH, predictors of cirrhosis varied according to ethnic background. Age was an independent predictor in both groups, however, AST/ALT ratio was found to be an independent predictor of cirrhosis only in Hispanic patients, and diabetes mellitus only in non-Hispanic patients.