Accuracy of international guidelines for identifying significant fibrosis in hepatitis B e antigen--negative patients with chronic hepatitis.

BACKGROUND & AIMS: Differing threshold levels of hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) are recommended by international guidelines for commencement of antiviral therapy. These guidelines advocate therapy for patients with significant fibrosis (METAVIR score ≥F2); we assessed the accuracy of these guideline-defined thresholds in identifying patients with ≥F2 fibrosis. METHODS: We applied the European (European Association for the Study of the Liver [EASL] 2012), Asian-Pacific (Asian-Pacific Association for the Study of the Liver [APASL] 2012), American (American Association for the Study of Liver Diseases [AASLD] 2009), and United States Panel Algorithm (USPA 2008) criteria to 366 consecutive hepatitis B e antigen-negative patients with liver biopsy samples: EASL, ALT >laboratory-defined upper limit of normal (ULN) and HBV DNA ≥2000 IU/mL (n = 171); APASL, ALT >2-fold laboratory-defined ULN and HBV DNA ≥2000 IU/mL (n = 87); AASLD, ALT >2-fold the updated ULN (0.5-fold ULN [corresponding to ≤19 U/L] for women and 0.75-fold the ULN [corresponding to ≤30 U/L] for men) and HBV DNA ≥20,000 IU/mL (n = 53); and USPA, ALT >updated ULN (>0.5-fold ULN for women and >0.75-fold ULN for men) and HBV DNA ≥2000 IU/mL (n = 173). RESULTS: Overall, 113 patients (30.9%) had ≥F2 fibrosis, which was more frequent among patients who fulfilled any guideline criteria (45.7% vs 17.9% for those who did not fulfill any criteria, P < .0001). In applying the EASL, AASLD, APASL, and USPA criteria, sensitivity and specificity values for detection of ≥F2 fibrosis were 45.6%, 58.5%, 56.3%, and 45.7% (P = .145) and 82.1%, 73.8%, 77.1%, and 82.4% (P = .366), respectively. The EASL criteria (area under the receiver operating characteristic [AUROC] curve, 0.66; 95% confidence interval [CI], 0.61-0.71) and USPA criteria (AUROC, 0.66; 95% CI, 0.58-0.73) performed better than APASL (AUROC, 0.64; 95% CI, 0.59-0.69; P = .421) and significantly better than the AASLD criteria (AUROC, 0.59; 95% CI, 0.54-0.64; P = .013). CONCLUSIONS: In hepatitis B e antigen-negative patients with chronic hepatitis, the EASL, AASLD, APASL, and USPA criteria identify patients with ≥F2 fibrosis with low levels of accuracy. However, the EASL and USPA criteria are the most accurate for identification of these patients.

Hepatocellular adenoma in glycogen storage disorder type I: a clinicopathological and molecular study.

AIMS: Glycogen storage disease type I is a metabolic disorder resulting from deficiency of the glucose-6-phosphate complex. Long-term complications include the development of hepatocellular adenoma (HCA). In this retrospective study, our aim was to reclassify according to geno-phenotypic characteristics nodular lesions identified in hepatectomy specimens of such patients transplanted between 1998 and 2008 at our institution. METHODS AND RESULTS: Clinicopathological data of seven consecutive transplanted patients with glycogen storage disease type I were reviewed. Liver nodules were re-examined histologically and by immunohistochemistry. Molecular analysis was performed additionally in a case with specific features. Four patients had multiple tumours. We concluded that 26 of 38 nodules available for study had features of inflammatory hepatocellular adenomas, seven comprised adenomas not otherwise specified and five were found to be focal nodular hyperplasia. CONCLUSIONS: Further studies are needed to clarify the pathogenesis of hepatocellular adenomas in glycogen storage disease; in particular to determine whether they share abnormal metabolic pathways with inflammatory adenomas in the general population. Testing for acute phase proteins may be a helpful tool in the early detection of HCA in such patients. Finally, there is a need to further define their risk of malignant transformation, in relation to age and possible cofactors.

Updated thresholds for alanine aminotransferase do not exclude significant histological disease in chronic hepatitis C.

BACKGROUND AND AIM: Histological changes in hepatitis C virus (HCV)-infected patients with persistently normal alanine aminotransferase (PNALT) have not been evaluated for updated upper limits of normal (ULN; ≤ 19/30 U/L for females/males). We assessed significant fibrosis (≥ F2, METAVIR) in patients with PNALT and persistently elevated alanine aminotransferase (PEALT). PATIENTS AND METHODS: Nine hundred and twenty consecutive, unselected HCV patients were stratified into four groups: Group I: (n = 124) PNALT within the updated ULN [0.5 × ULN (corresponding to ≤ 19 U/L) for females; 0.75 × ULN (corresponding to ≤ 30 U/L) for males]; Group II (n = 173): PNALT ≤ 1 × ULN but greater than Group I; Group III (n = 313): PEALT 1-2 × ULN; and Group IV (n = 310): PEALT > 2 × ULN. PNALT was defined as ≥ 3 determinations within the normal range over ≥ 6 months. RESULTS: Advanced ≥ F3 and ≥ F2 fibrosis increased incrementally across Groups I; II; III; and IV: 24.2 and 45.2%; 25.4 and 56.1%; 36.1 and 64.2%; and 50 and 77.1% respectively (P<0.0001 for both). Multivariable logistic regression analysis identified age [odds ratio (OR), 1.05; 95% confidence intervals (CI): 1.02-1.08; P<0.0001], alanine aminotransferase (ALT) groups (OR 1.38; 95% CI: 1.03-1.83; P = 0.030), presence of moderate-severe steatosis (OR 2.70; 95% CI: 1.19-6.15; P = 0.018) and ≥ A2 necroinflammation (OR 17.9; 95% CI: 8.88-36.20; P < 0.0001) as independent predictors of ≥ F2 fibrosis. Updated ULN for ALT were better at excluding ≥ F2 fibrosis compared with traditional ULN (90.6 vs. 74.2%, P = 0.0041) but less specific (20.8 vs. 44%, P = 0.0007) with similar positive/negative predictive values. CONCLUSIONS: HCV patients with 'updated' normal ALT have the lowest prevalence of significant fibrosis, although utilizing these levels without resorting to biopsy would miss significant fibrosis in almost one-half of such patients.

Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families.

BACKGROUND & AIMS: Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. METHODS: Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. RESULTS: Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]). CONCLUSIONS: With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential.

A Case of Eosinophilic Gastroenteritis Associated with Eosinophilic Ascites Diagnosed by Full-Thickness Biopsy of the Small Intestine.

BACKGROUND Eosinophilic gastroenteritis is a rare disease, characterized by infiltrates of eosinophils in the intestinal mucosa, muscularis propria, and serosa. Eosinophilic gastroenteritis is due to Type 1 hypersensitivity and can be associated with other atopic diseases. The clinical course of eosinophilic gastroenteritis varies depending on the location, extent, and depth of eosinophilic infiltration of the gastrointestinal tract, which can make the diagnosis challenging. A case of eosinophilic gastroenteritis associated with eosinophilic ascites is presented that emphasizes the importance of full-thickness intestinal biopsy, which includes the muscularis propria, to allow the definitive diagnosis to be made. CASE REPORT A 28-year-old man presented with vague abdominal pain, nonspecific gastrointestinal symptoms, unintentional weight loss, and progressive ascites during the previous several months. A diagnosis of eosinophilic gastroenteritis was made after the exclusion of other possible causes, which was confirmed by histopathology of a full-thickness intestinal biopsy. The patient was treated with steroids. At one-month follow-up, the patient reported reduced abdominal pain. CONCLUSIONS A case of eosinophilic gastroenteritis associated with eosinophilic ascites is presented that emphasizes the importance of full-thickness intestinal biopsy, which includes the muscularis propria, to allow the definitive diagnosis to be made.

Is serum alanine transaminase level a reliable marker of histological disease in chronic hepatitis C infection?

BACKGROUND: Approximately 20-30% of patients chronically infected with hepatitis C virus (HCV) have persistently normal alanine transaminase (PNALT) levels. These patients are described to have a mild degree of histological liver damage. We aimed to assess the histological liver changes in HCV patients with PNALT. PATIENTS AND METHODS: Sixty-five patients with HCV and PNALT (group A) underwent a liver biopsy. PNALT was defined as three or more determinations identified to be within the normal range over 6 months or longer. The demographical features and histological changes were compared with 66 consecutive patients with chronic HCV infection and elevated ALT (group B). All patients had a detectable HCV RNA. Histological disease was scored according to the METAVIR system. RESULTS: Females were more likely to have normal ALT levels (65%). The mean ALT level in Group A and B was 30 and 105 IU/L respectively. No patient in either group had normal histology. The mean necro-inflammatory scores in groups A and B (2.0+/-0.68 vs 2.09+/-0.67) and the mean fibrosis scores (2.11+/-0.87 vs 2.24+/-1.04) were not significantly different. Bridging fibrosis in groups A and B was seen in 24.6 and 37.9% patients, respectively, while cirrhosis was seen in 6.2 and 7.6% patients respectively. Hepatic steatosis in groups A and B (0.94+/-0.86 vs 1.0+/-1.02 respectively) was also not significantly different and did not show any association with the fibrosis scores across the two groups. In group A, the necro-inflammatory and fibrosis scores of patients with and without steatosis were not statistically significant. Age was the only predictor of normal ALT levels. However, increasing age did not show a significant increase in histological activity in either group beyond a certain age. CONCLUSION: This study demonstrates that ALT is a poor surrogate marker for inflammation and fibrosis in HCV patients. Given the presence of significant necro-inflammation in PNALT patients, the risk/benefit ratio justifies treatment without the need for a liver biopsy.

Aggressive Recurrence of Primary Hepatic Epithelioid Haemangioendothelioma after Liver Transplantation.

HEHE is a rare neoplasm of vascular origin that occurs in the liver; UNOS reported a favorable outcome after liver transplantation in 110 patients with 1-year and 5-year survival of 80% and 64%. Case Report. A 40-year-old lady presented with a three-month history of right upper abdominal pain with nausea, vomiting, and significant loss of weight associated with scleral icterus and progressive abdominal distension. Examination revealed jaundice, hepatomegaly, and ascites. Serum bilirubin was 26.5 mg/dL and ALP was 552 CT. Abdomen and pelvis showed diffuse infiltrative neoplastic process of the liver with a mass effect and stretching of the hepatic and portal veins, in addition to bile duct dilatation. Viral hepatitis markers were negative and serum alpha fetoprotein was within reference range. Liver biopsy was consistent with HEHE, with positive endothelial markers (CD31, CD34, and factor VIII-related antigen). She underwent living related liver transplantation on June 2013 and was discharged after 20 days with normal liver enzymes. Four months later, she presented with diffuse disease recurrence. Liver biopsy confirmed disease recurrence; she received supportive treatment and unfortunately she died 2 weeks later. Conclusion. HEHE can have rapid and aggressive recurrence after liver transplantation.

Hepatic inflammatory pseudotumor presenting in an 8-year-old boy: A case report and review of literature.

Hepatic inflammatory pseudotumors are uncommon benign lesions. Accurately diagnosing hepatic inflammatory pseudotumor can be very challenging because the clinical presentation and radiological appearances are nonspecific and cannot be certainly distinguished from malignant neoplastic processes. Herein, we present a case of hepatic IPT in an 8-year-old boy who presented to clinic with a 3-mo history of a tender hepatic mass, fever of unknown origin, and 9-kg weight loss. The physical examination was notable for tender hepatomegaly. Laboratory investigations were notable for a normal hepatic profile and elevated erythrocyte sedimentation rate and C-reactive protein. A T2-attenuated magnetic resonance imaging scan of the abdomen showed a 4.7 cm × 4.7 cm × 6.6 cm, contrast-enhancing, hyper-intense, well-defined lesion involving the right hepatic lobe. In view of the unremitting symptoms, tender hepatomegaly, thrombosed right hepatic vein, nonspecific radiological findings, and high suspicion of a deep-seated underlying infection or malignancy, a right hepatic lobectomy was recommended. Microscopically, the hepatic lesion exhibited a mixture of inflammatory cells (histiocytes, plasma cells, mature lymphocytes, and occasional multinucleated giant cells) in a background of dense fibrous tissue. Immunohistochemically, the cells stained negative for SMA, ALK-1, CD-21 and CD-23, diffusely positive for CD-68, and focally positive for IgG4. The final histopathological diagnosis was consistent with hepatic IPT. At the postoperative 4-mo follow-up, the patient was asymptomatic without radiological evidence of recurrence.

Pediatric living-related liver transplantation in Saudi Arabia.

OBJECTIVE: The purpose of this paper is to report our experience of the first 29 consecutive living-related liver transplants in pediatric recipients and to demonstrate the feasibility of living-related liver transplantation in the Arab World. The first living-related liver transplantation in the Kingdom of Saudi Arabia was performed in November 1998 by Bassas et al following an appropriate period of multi-disciplinary preparation. METHODS: This study was carried out at the Armed Forces Hospital, Riyadh, Kingdom of Saudi Arabia, during the period November 1998 through to October 2001. A review of the data of the transplanted children and adult donors was carried out. The data recorded for recipients included age, sex, patient's weight, preoperative diagnosis, intraoperative surgical complications, graft size and weight, medical and surgical postoperative complications, immunosuppression, rejection and overall survival rate. Data recorded for the donors included age, sex and any postoperative complications. RESULTS: The most frequent indication for living-related liver transplantation in our series was metabolic liver disease. Post-operative complications included biliary leaks in 10% (N=3), vascular occlusion in 13% (N=4), acute cellular rejection in 38% (N=11), positive cytomegalovirus PP65 antigen in 38% (N=11), wound infection in 3.4% (N=one), and systemic infections in 14% (N=4). One urgent retransplantation was necessary due to thrombosis of the hepatic artery. Patient and graft survival rates are 96% and 93%. One patient, treated for acute liver failure, died 2 months post-transplant. CONCLUSION: Our experience has shown pediatric living-related liver transplantation to be a success whilst alleviating the need for sending Saudi patients overseas for treatment and providing a solution to organ shortages for pediatric patients. In general, this endeavor has broadened the spectrum of our experience in surgery, anesthetics, intensive care and pediatrics.

Desmoplastic small round cell tumor of stomach.

Desmoplastic small round cell tumor (DSRCT) is an extremely uncommon, highly aggressive, and malignant mesenchymal neoplasm of undetermined histogenesis. Less than 200 case reports have been documented in literature so far. Herein, we report a 26-year-old otherwise healthy female patient who presented with a 1-month history of epigastric pain. On physical examination, a palpable, slightly mobile, and tender epigastric mass was detected. All laboratory tests were normal. A chest, abdominal, and pelvic contrast-enhanced computed tomography (CT) scans showed a 3.8 × 7.2 × 8.7 cm ill-defined mass, involving gastric fundus and extending into gastric cardia and lower gastroesophageal junction. It was associated with multiple enlarged gastrohepatic lymph nodes; the largest measured 1.2 cm. There was no evidence of ascites or retroperitoneal or mesenteric lymphatic metastases. Patient underwent total gastrectomy with D2 lymphadenectomy, splenectomy, and antecolic Roux-en-Y esophagojejunal anastomosis. Histopathological examination revealed coexpression of mesenchymal, epithelial, and neural markers. The characteristic chromosomal translocation (t(11; 22)(p13; q12)) was demonstrated on fluorescence in situ hybridization (FISH) technique. Diagnosis of DSRCT of stomach was confirmed. Patient received no postoperative radiotherapy or chemotherapy. A postoperative 3-month followup failed to show any recurrence. In addition, a literature review on DSRCT is included.

Antibody-mediated rejection: importance of lactate dehydrogenase and neutrophilia in early diagnosis.

We report the importance of elevated serum lactate dehydrogenase (LDH) and neutrophilia (NT) in two renal transplant recipients who developed renal impairment in the early post-operative period. One of our recipients developed oliguria and increased serum creatinine with unexplained elevation of LDH and NT. The biopsy was C4d positive with platelet and fibrin thrombi in the glomerular capillaries and arterioles and interpreted as acute vasculitis or thrombotic form of antibody-mediated rejection (VAMR) with positive donor-specific antibodies (DSA). Despite intensive treatment, this graft was lost. When another patient developed a similar picture, prompt immunoadsorption was started without waiting for a confirmatory biopsy or DSA, and both were later reported as positive. Improvement in renal function was associated with decreasing levels of LDH and NT. Neither of these was elevated in cases of acute cellular rejection (ACR) or antibody mediated rejection (AMR) with isolated tubular injury (TAMR). It may therefore be reasonable to assume that LDH and NT are potential diagnostic and prognostic markers of VAMR.

Chromium chloride administration causes a substantial reduction of coronary lipid deposits, aortic lipid deposits, and serum cholesterol concentration in rabbits.

This experiment was carried out to test the null hypothesis that intramuscular trivalent chromium administration would not remove lipids from the heart and ascending aorta of the hyoercholesterolemic rabbits and would not lower their serum cholesterol levels. A novel computer-based method, previously described, was used to assess the sizes of the intracardiac and aortic lesions. Clinical chemistry and histopathology were performed through routine methods. The sizes of the lipid deposits in the coronary vasculature of the hypercholesterolemic rabbits were greatly reduced as a result of the intramuscular chromium chloride injections. Lipid deposits in the ascending aorta were similarly reduced, as well as the serum cholesterol concentrations. The terminal serum chromium concentrations in the chromium-treated group were in the range of 3,258-4,513 microg/L, whereas, in the untreated animals, the concentrations were 3.2 to 6.3 microg/L. The general condition of the chromium-treated animals was good and they were continuing to gain weight up to the time they were killed. However, it was found that their liver function tests had become abnormal even though there was no evidence of hepatic histopathological lesions specifically affecting the chromium-treated group. The kidney function tests and histopathology were normal. These findings suggest that a more aggressive approach than those tried hitherto might be useful in treating atherosclerotic human patients with chromium.