Abnormal liver function in common variable immunodeficiency disorders due to nodular regenerative hyperplasia.

Patients with common variable immunodeficiency disorders are monitored for liver function test abnormalities. A proportion of patients develop deranged liver function and some also develop hepatomegaly. We investigated the prevalence of abnormalities and types of liver disease, aiming to identify those at risk and determine outcomes. The local primary immunodeficiency database was searched for patients with a common variable immunodeficiency disorder and abnormal liver function and/or a liver biopsy. Patterns of liver dysfunction were determined and biopsies reviewed. A total of 47 of 108 patients had deranged liver function, most commonly raised alkaline phosphatase levels. Twenty-three patients had liver biopsies. Nodular regenerative hyperplasia was found in 13 of 16 with unexplained pathology. These patients were more likely to have other disease-related complications of common variable immunodeficiency disorders, in particular non-coeliac (gluten insensitive) lymphocytic enteropathy. However, five had no symptoms of liver disease and only one died of liver complications. Nodular regenerative hyperplasia is a common complication of common variable immunodeficiency disorders but was rarely complicated by portal hypertension.

Hipertricosis cubital. Descripción de dos casos / Two cases of hypertrichosis cubiti

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EpCAM and gpA33 are markers of Barrett's metaplasia.

AIMS: To characterise a specific and sensitive marker of Barrett's metaplasia (BM). METHODS: Cases of normal oesophageal squamous mucosa (11 fresh endoscopic biopsies and 10 formalin fixed, paraffin embedded tissue blocks), BM (11 biopsies and 11 tissue blocks), and normal gastric body mucosa (five biopsies and five tissue blocks) were analysed using reverse transcriptase PCR, Western blotting, and immunohistochemistry for EpCAM, and reverse transcriptase PCR for gpA33. RESULTS: Strong EpCAM mRNA expression was detected in all the BM cases, in contrast to weak expression in all the normal gastric mucosal samples and no expression in any of the normal oesophageal mucosal samples tested. Strong gpA33 mRNA expression was detected in all the BM cases, in contrast to weak expression in a quarter of the normal gastric mucosal samples and no expression in any of the normal oesophageal mucosal samples tested. Western blotting showed EpCAM protein expression in all the BM cases and in none of the normal gastric or oesophageal mucosal samples tested. Immunohistochemistry showed strong EpCAM protein expression in BM and complete absence of expression in normal oesophageal squamous epithelium. Scattered EpCAM expressing cells were found in the gland bases of normal gastric body mucosa. CONCLUSIONS: EpCAM protein and gpA33 mRNA expressions are specific and sensitive markers of BM.

CDX1 is an important molecular mediator of Barrett's metaplasia.

The molecular pathogenesis of Barrett's metaplasia (BM) of the esophagus is poorly understood. The change to an intestinal phenotype occurs on a background of esophagitis due to refluxing acid and bile. CDX1, an important regulator of normal intestinal development, was studied as a potential key molecule in the pathogenesis of BM. CDX1 mRNA and protein were universally expressed in all samples of BM tested but not in normal esophageal squamous or gastric body epithelia. This tissue-specific expression was attributable to the methylation status of the CDX1 promoter. Conjugated bile salts and the inflammatory cytokines TNF-alpha and IL-1beta were all found to increase CDX1 mRNA expression in vitro. These effects were primarily mediated by NF-kappaB signaling but only occurred when the CDX1 promoter was unmethylated or partially methylated. The data suggest that CDX1 is a key molecule linking etiological agents of BM to the development of an intestinal phenotype. Although the initial trigger for CDX1 promoter demethylation is not yet identified, it seems likely that demethylation of its promoter may be the key to the induction and maintenance of CDX1 expression and so of the BM phenotype.

Treatment of hepatic metastases of neuroendocrine malignancies: a 10-year experience.

BACKGROUND: Liver metastases from neuroendocrine tumours may give rise to symptoms due to hormone production or mass effect. Accepted management options include administration of somatostatin-analogues, selective chemoembolisation or hepatic resection. The aim of this study was to review the management of hepatic neuroendocrine metastases in our unit. METHODS: Patients with neuroendocrine tumours presenting between 1989 and 1999 were identified from pathology, radiology and surgical databases. Case notes were retrospectively reviewed for demographic data, treatment modality and outcome. Response to treatment was based on biochemistry, radiology or symptoms, and response rates were defined accordingly. RESULTS: Thirty patients with a mean age of 55 years presented with, or later developed liver metastases. The most frequent presenting symptoms were abdominal pain (63%), diarrhoea (40%), weight loss (33%) and flushing (13%). Five patients underwent liver resection with complete symptomatic response, nine underwent chemoembolisation with a 75% response rate (either biochemically, radiologically or symptomatic) and fifteen were treated with a somatostatin-analogue, with a response rate of 86%. Median survival from detection of metastases was 45 months. CONCLUSIONS: Liver resection provides good symptomatic relief, but it is only indicated in a small proportion of patients with metastatic neuroendocrine tumours. Both chemoembolisation and somatostatin-analogues offer useful symptomatic control for these patients with good survival prospects.

Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes.

Juvenile polyposis syndrome (JPS) is an inherited hamartomatous-polyposis syndrome with a risk for colon cancer. JPS is a clinical diagnosis by exclusion, and, before susceptibility genes were identified, JPS could easily be confused with other inherited hamartoma syndromes, such as Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden syndrome (CS). Germline mutations of MADH4 (SMAD4) have been described in a variable number of probands with JPS. A series of familial and isolated European probands without MADH4 mutations were analyzed for germline mutations in BMPR1A, a member of the transforming growth-factor beta-receptor superfamily, upstream from the SMAD pathway. Overall, 10 (38%) probands were found to have germline BMPR1A mutations, 8 of which resulted in truncated receptors and 2 of which resulted in missense alterations (C124R and C376Y). Almost all available component tumors from mutation-positive cases showed loss of heterozygosity (LOH) in the BMPR1A region, whereas those from mutation-negative cases did not. One proband with CS/CS-like phenotype was also found to have a germline BMPR1A missense mutation (A338D). Thus, germline BMPR1A mutations cause a significant proportion of cases of JPS and might define a small subset of cases of CS/BRRS with specific colonic phenotype.

Histopathological grade, mucinous differentiation and DNA ploidy in relation to prognosis in colorectal carcinoma.

AIMS: We investigated parameters which might help identify poor prognosis colorectal cancers and, in particular, we stratified Dukes' stage B carcinomas in order to identify those patients who would benefit from adjuvant therapy. METHODS AND RESULTS: Histopathological parameters and DNA ploidy were analysed in a consecutive series of 256 resected colorectal cancers and their relationship with patient survival were investigated. By univariate analysis, Dukes' stage, degree of differentiation, nature of the invasive margin and DNA ploidy all correlated with prognosis. However, degree of differentiation assessed by the worst pattern seen anywhere in the tumour correlated more significantly with clinical outcome than did the predominant pattern. This was confirmed by multivariate analysis which showed only Dukes' stage and worst pattern differentiation as independent prognostic variables. Mucinous carcinomas showed no significant difference in outcome when compared to adenocarcinomas. DNA ploidy correlated with prognosis but only at a low level (P = 0.035) but this was maintained for Dukes' B carcinomas. CONCLUSIONS: Dukes' stage and degree of differentiation provide independent prognostic information in colorectal cancer. However, differentiation should be assessed by the worst pattern and not by the predominant pattern as is currently recommended by the UKCCCR. DNA ploidy provides some prognostic information and does stratify Dukes' B cancers and thus might provide useful information on which to base decisions concerning adjuvant therapies in this difficult group. Mucinous differentiation has no prognostic significance.

Assessment of liver histology in patients with hepatitis C and normal transaminase levels.

OBJECTIVE: To compare liver histology in patients with hepatitis C infection (HCV) between patients with normal and abnormal alanine aminotransferase (ALT) and examine its relationship with HCV genotype and route of infection. METHODS: One hundred consecutive patients with known HCV presenting for diagnostic laparoscopy and liver biopsy were studied. Route of infection was noted and ALT measured on the day of biopsy and HCV genotype determined. Hepatic pathology was analysed using the Edinburgh scoring system (ESS). RESULTS: Fifteen patients had normal ALT, of whom three (20%) had cirrhosis and 10 (66.7%) fibrosis. Of patients with raised ALT, cirrhosis and fibrosis were similarly found in 14 (16.5%) and 62 (72.9%) respectively. Severe, moderate and mild inflammation occurred in one (6.7%), four (26.7%) and 10 (66.6%) patients with normal ALT compared with 17 (20%), 50 (58.8%) and 18 (21.2%) of those with raised ALT (P < 0.01). There was no significant difference in age, route of infection or genotype between those with normal and raised ALT levels. CONCLUSION: Of patients with normal ALT at time of liver biopsy, a significant minority have cirrhosis or significant hepatic inflammation. Liver biopsy is essential in HCV infection as a guide to both therapy and prognosis.

Investigation of chronic hepatitis C infection in individuals with haemophilia: assessment of invasive and non-invasive methods.

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease in individuals with haemophilia. A wide spectrum of disease severity is found in this group, ranging from mild hepatitis to cirrhosis. We have studied a cohort of 87 anti-HCV positive haemophiliacs who have been infected with HCV for 10-25 years and assessed the relative value of invasive and non-invasive methods of evaluating liver disease. The severity of liver disease was assessed using ultrasound scan (n = 77), upper GI endoscopy (n = 50), laparoscopic liver inspection (n = 33) and liver biopsy (n = 22). Invasive investigations were performed without any significant bleeding complications. Evidence of severe liver disease was found in approximately 25% of patients. There was agreement between the severity of liver histology and the information derived from the laparoscopic liver inspection, endoscopy and ultrasound in 86%. Co-infection with HIV was significantly associated with more severe liver disease (P = 0.006). This study provides further evidence that liver disease is emerging as a major complication in haemophiliacs and severe liver disease is more common in those co-infected with HIV. We have shown the potential value of laparoscopic liver inspection, in combination with endoscopy and ultrasound, in staging the extent of liver disease, and suggest that most patients may be managed without resorting to liver biopsy.

Interferon treatment for chronic hepatitis C infection in hemophiliacs--influence of virus load, genotype, and liver pathology on response.

In this study, we assessed the effectiveness of interferon treatment in 31 hemophiliacs with chronic hepatitis C virus (HCV) infection. Interferon alfa-2a (3 MU three times weekly) was administered for 6 months. Response was assessed by both serial alanine transaminase (ALT) and HCV RNA levels measured by a sensitive semiquantitative polymerase chain reaction (PCR) method. HCV genotype was determined by restriction fragment length polymorphism (RFLP), and evidence of changing genotypes during interferon therapy was sought. Severity of liver disease was assessed by both noninvasive and invasive methods, including laparoscopic liver inspection and biopsy. Sustained normalization of ALT levels occurred in eight patients (28%), and seven (24%) became nonviremic as assessed by PCR (<80 HCV/mL). Responders universally cleared HCV RNA within 2 months of starting interferon. Genotype 3a was associated with a favorable response to interferon. No evidence was found for a change in circulating genotype in patients who failed to respond to interferon or who relapsed. This study confirms that response rates to interferon are low in hemophiliacs as compared with other groups with chronic HCV infection. We have also demonstrated that virus load measurement over the first 8 to 12 weeks of treatment is an extremely useful method to identify responders at an early stage.

Primary pulmonary hypertension developing 11 years after a splenorenal shunt for portal hypertension in hepatic cirrhosis.

OBJECTIVE: To describe a patient with pulmonary and portal hypertension and to review the pathogenesis and management of this condition. PATIENT: A 22-year-old woman with portal hypertension and liver cirrhosis who later developed pulmonary hypertension. INTERVENTIONS: The patient received antibiotic therapy and underwent a splenectomy and proximal splenorenal shunt for portal hypertension. She later received hydralazine, digoxin and warfarin for pulmonary hypertension. MAIN OUTCOME MEASURES: After undergoing a splenorenal shunt the patient made a good recovery. However, she later developed pulmonary hypertension and died after undergoing a hysterectomy and a bilateral salpingo-oophorectomy. CONCLUSIONS: The concomitant development of portal and pulmonary hypertension in the same patient has a poor prognosis. The treatment available for patients with these conditions is unsatisfactory and most patients eventually die as a result of cardiovascular disease. Cardiopulmonary and liver transplantation should be considered in suitable patients.