Alessandra Forgione

Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease

The role played by the gut in nonalcoholic fatty liver disease (NAFLD) is still a matter of debate, although animal and human studies suggest that gut‐derived endotoxin may be important. We investigated intestinal permeability in patients with NAFLD and evaluated the correlations between this phenomenon and the stage of the disease, the integrity of tight junctions within the small intestine, and prevalence of small intestinal bacterial overgrowth (SIBO). We examined 35 consecutive patients with biopsy‐proven NAFLD, 27 with untreated celiac disease (as a model of intestinal hyperpermeability) and 24 healthy volunteers. We assessed the presence of SIBO by glucose breath testing (GBT), intestinal permeability by means of urinary excretion of 51Cr‐ethylene diamine tetraacetate (51Cr‐EDTA) test, and the integrity of tight junctions within the gut by immunohistochemical analysis of zona occludens‐1 (ZO‐1) expression in duodenal biopsy specimens. Patients with NAFLD had significantly increased gut permeability (compared with healthy subjects; P < 0.001) and a higher prevalence of SIBO, although both were lower than in the untreated celiac patients. In patients with NAFLD, both gut permeability and the prevalence of SIBO correlated with the severity of steatosis but not with presence of NASH. Conclusions: Our results provide the first evidence that NAFLD in humans is associated with increased gut permeability and that this abnormality is related to the increased prevalence of SIBO in these patients. The increased permeability appears to be caused by disruption of intercellular tight junctions in the intestine, and it may play an important role in the pathogenesis of hepatic fat deposition. (HEPATOLOGY 2009.)

Nonalcoholic fatty liver disease is associated with increased GHBP and reduced GH/IGF-I levels

Introduction  Nonalcoholic fatty liver disease (NAFLD) has been described in adult GH deficiency syndrome. Furthermore, chronic liver disease can be associated with significant changes in levels of IGF‐I, GH‐binding protein (GHBP), IGF‐binding proteins (IGFBPs) and acid‐labile subunit (ALS). However, the effect of liver steatosis on the GHBP production has not been investigated yet.

Serum levels of hyaluronic acid and tissue metalloproteinase inhibitor-1 combined with age predict the presence of nonalcoholic steatohepatitis in a pilot cohort of subjects with nonalcoholic fatty liver disease

Hyaluronic acid (HA) and tissue inhibitor of metalloproteinase 1 (TIMP-1) are reliable markers of liver fibrosis and are closely linked to the proinflammatory status. In this pilot cohort study, we attempted to identify a clinical score that would predict the severity of nonalcoholic fatty liver disease (NAFLD) based on clinical variables and serum markers of fibrosis and inflammation. The cohort included 46 patients with histologically confirmed NAFLD (76.1% male; mean age, 43+/-13 years; mean body mass index [BMI], 27.8+/-3.5). Serum transforming growth factor beta (TGF-beta), HA, TIMP, and matrix metalloproteinase (MMP) levels were measured with commercial enzyme-linked immunoassay (ELISA) kits. Demographic features and clinical and laboratory findings were subjected to univariate and multivariate binary logistic regression analysis to construct the mathematical model. Receiver operating characteristic curve (ROC) analysis was used to identify a threshold value for diagnosis of NASH and to assess its sensitivity and specificity. Serum levels of HA and TIMP-1 were statistically different in patients with nonalcoholic steatohepatitis (NASH) (P<0.05). Logistic regression analysis of several clinical variables indicated patient age as the only independent predictor of NASH (odds ratio [OR], 1.129, 95% confidence interval [CI], 1.019-1.251, P=0.020). The mathematical model constructed on the basis of these results included age, TIMP-1, and HA levels. A value of 148.27 or more identified patients with NASH with 85.7% sensitivity, 87.1% specificity, and negative and positive predictive values of 96.4% and 60%, respectively. This model seems to represent a reliable noninvasive tool for excluding the presence of NASH. If validated in larger prospective cohort studies, it might be useful for determining when a liver biopsy is actually warranted in patients with NAFLD.

Mild hepatitis at recommended doses of acetaminophen in patients with evidence of constitutionally enhanced cytochrome P450 system activity

Acetaminophen (paracetamol) is used throughout the world for pain relief and antipyresis in both children and adults. In many countries, it can be purchased without a medical prescription and it is also a common component of a number of over‐the‐counter remedies for colds, influenza and the like. Fasting, malnutrition and use of alcohol and/or other drugs are thought to play causal roles in hepatotoxicity associated with recommended doses of acetaminophen although liver injury provoked by therapeutic doses has also been observed in the absence of these factors. We describe two patients who experienced subclinical hepatotoxic reactions after taking acetaminophen at therapeutic doses. The results of an antipyrine metabolism test suggest the presence of constitutional hyperactivity of the cytochrome P450‐dependent mixed function oxidative system in both patients. We hypothesize that the latter contributed to the hepatotoxicity and that it may play a role in idiosyncratic reactions to this drug.

anticholinergic syndrome due to " Devil's herb': when risks come from the ancient time

We describe a case of Mandragora autumnalis poisoning which occurred in a 72‐year‐old female patient who had eaten the venenous M. Autumnalis, picked near her home, mistaking it for the edible Borago Officinalis. M. Autumnalis is a solanaceous plant, common in the Sicilian countryside, which contains a variable concentration of solanum alkaloids, causing gastrointestinal irritation, and tropane alkaloids, with anticholinergic properties. Unluckily, M. Autumnalis is often mistaken for the edible B. Officinalis, likewise widespread in Sicilian countryside. The diagnosis of Mandragora poisoning was made on the basis of clinical symptoms and signs of anticholinergic syndrome associated with a history of vegetable meal of uncontrolled origin, moreover analysing the vegetable obtained from gastric lavage. Decontamination and symptomatic treatment were useful in our patient to control acute poisoning.

Severe veno‐occlusive disease after autologous peripheral blood stem cell transplantation for high‐grade non‐Hodgkin lymphoma: report of a successfully managed case and a literature review of veno‐occlusive disease

Abstract:  Veno‐occlusive disease (VOD) of the liver is a severe complication of high‐dose chemotherapy and allogeneic or autologous stem cell transplantation with potential fatal outcome. We report a case of severe VOD in a patient with a high‐grade B‐cell lymphoma. Liver‐venule occlusion was confirmed by liver biopsy. Supportive care, fibrinolytic treatment with recombinant tissue plasminogen activator and defibrotide maintenance therapy led to complete resolution of VOD demonstrated at liver biopsy and with a follow‐up of 44 months after autologous peripheral blood stem cell transplantation. The literature on VOD has been reviewed.

Thromboembolism and breast cancer: the hidden risk for patient and physician

A 65-year-old woman presented 2 weeks after neurosurgery with the sudden onset of dyspnoea and a 7-day history of pain and swelling of her right leg. She had a history of ductal carcinoma of the breast (pT2, pN1b, M0; G3; ER 80%, PR 20%) treated with radical mastectomy in 1995, adjuvant chemotherapy (cyclophosphamide, methotrexate and fluorouracil) and tamoxifen for 5 years with remission. In 2004, she presented with a sensory deficit, vertigo and ataxia. Magnetic resonance imaging of the brain showed a right frontal lobe lesion compatible with metastatic breast cancer and she underwent neurosurgical interventionwithout immediate complications. In the emergency room, physical examination showed warm erythema with pain and swelling of the

NON-INVASIVE ASSESSMENT OF HISTOLOGICAL INFLAMMATION IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)

Methods: We retrospectively reviewed all clinical records of patients with DILI admitted to our Unit from February 1996 to December 2006. A database was constructed, reporting data regarding age, sex, clinical features at onset, laboratory results, suspected drugs and follow-up. The diagnosis of DILI was based on the presence of at least three of the International Consensus Criteria (J Hepatol 1990). Liver damage was defined as hepatocellular, cholestatic or mixed, according to clinical and laboratory data, since histology was performed only in a minority of patients. All patients were negative for hepatitis A, B, C, EBV and CMV serology and non organ-specific autoantibody screening. Results: Forty six cases out of 6,134 patients received a discharge diagnose of DILI. There were 23 men and 23 women, mean age was 54.2 (range 11-88 yrs), 35 patient (74%) were older than 40 years. Five patients had an associated chronic liver disease (2 cirrhosis and 3 HCV-related chronic hepatitis). At clinical presentation all patients had abnormal liver function tests (LFTs), 22 patients were jaundiced and 3 patients was admitted for hepatic failure, manifest as hepatic encephalopathy. Liver damage was hepatocellular in 19 patients, cholestatic in 15 and mixed in 12. In 10 (22%) of cases, two or more drugs were involved. NSAIDs (n =17), psychotropic drugs (n =7) and antibiotics (n =10) were the most commonly involved drugs, followed by anti-platelet, anti-diabetic drugs and statins. NSAIDs were involved in three cases of acute liver failure and, among them, one was listed for liver transplantation but died while on the waiting list. All patients had regular follow-up visits every three months for at least one year after discharge. All patients, including those with pre-existing liver disease had a complete normalization of LFTs at the end of follow-up. Conclusions: Severe DILI requiring hospital admission is very rare and appears more common in patients over 40 years. NSAIDs, psychotropic drugs and antibiotics are the most common responsible drugs. Even in severe cases, recovery is almost the rule and only a few patients have an unfavourable course and eventually die