The Natural History of Severe Acute Liver Injury.

OBJECTIVES: Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS: 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS: Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS: A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies.

BACKGROUND: The goal of hepatorenal syndrome type 1 (HRS-1) treatment is to improve renal function. Terlipressin, a synthetic vasopressin analogue, is a systemic vasoconstrictor used for the treatment of HRS-1, where it is available. AIM: To compare the efficacy of terlipressin plus albumin vs. placebo plus albumin in patients with HRS-1. METHODS: Pooled patient-level data from two large phase 3, randomised, placebo-controlled studies were analysed for HRS reversal [serum creatinine (SCr) value ≤133 µmol/L], 90-day survival, need for renal replacement therapy and predictors of HRS reversal. Patients received intravenous terlipressin 1-2 mg every 6 hours plus albumin or placebo plus albumin up to 14 days. RESULTS: The pooled analysis comprised 308 patients (terlipressin: n = 153; placebo: n = 155). HRS reversal was significantly more frequent with terlipressin vs. placebo (27% vs. 14%; P = 0.004). Terlipressin was associated with a more significant improvement in renal function from baseline until end of treatment, with a mean between-group difference in SCr concentration of -53.0 µmol/L (P < 0.0001). Lower SCr, lower mean arterial pressure and lower total bilirubin and absence of known precipitating factors for HRS were independent predictors of HRS reversal and longer survival in terlipressin-treated patients. CONCLUSIONS: Terlipressin plus albumin resulted in a significantly higher rate of HRS reversal vs. albumin alone in patients with HRS-1. Terlipressin treatment is associated with improved renal function. (ClinicalTrials.gov identifier: OT-0401, NCT00089570; REVERSE, NCT01143246).

Fluid retention in cirrhosis: pathophysiology and management.

Accumulation of fluid as ascites is the most common complication of cirrhosis. This is occurring in about 50% of patients within 10 years of the diagnosis of cirrhosis. It is a prognostic sign with 1-year and 5-year survival of 85% and 56%, respectively. The most acceptable theory for ascites formation is peripheral arterial vasodilation leading to underfilling of circulatory volume. This triggers the baroreceptor-mediated activation of renin-angiotensin-aldosterone system, sympathetic nervous system and nonosmotic release of vasopressin to restore circulatory integrity. The result is an avid sodium and water retention, identified as a preascitic state. This condition will evolve in overt fluid retention and ascites, as the liver disease progresses. Once ascites is present, most therapeutic modalities are directed on maintaining negative sodium balance, including salt restriction, bed rest and diuretics. Paracentesis and albumin infusion is applied to tense ascites. Transjugular intrahepatic portosystemic shunt is considered for refractory ascites. With worsening of liver disease, fluid retention is associated with other complications; such as spontaneous bacterial peritonitis. This is a primary infection of ascitic fluid caused by organisms originating from large intestinal normal flora. Diagnostic paracentesis and antibiotic therapy plus prophylactic regimen are mandatory. Hepatorenal syndrome is a state of functional renal failure in the setting of low cardiac output and impaired renal perfusion. Its management is based on drugs that restore normal renal blood flow through peripheral arterial and splanchnic vasoconstriction, renal vasodilation and/or plasma volume expansion. However, the definitive treatment is liver transplantation.

Wilson disease--a practical approach to diagnosis, treatment and follow-up.

Wilson disease is an inherited, autosomal recessive, copper accumulation and toxicity disorder that affects about 30 individuals per million. This rare disease is caused by mutations in the gene encoding a copper-transporting P-type ATPase, which is important for copper excretion into bile, leading to copper accumulation in the liver. Toxic copper concentrations can also be found in the brain and kidney, and clinical phenotypes include hepatic, haemolytic, neurologic and psychiatric diseases. Diagnosis is based on the combination of clinical features and findings such as increased urinary copper excretion, reduced levels of serum ceruloplasmin, high concentrations of copper in liver tissues and Kayser-Fleischer rings. Genetic studies are also becoming available for clinical use, but the utility of direct mutation analysis is limited. Wilson disease can be treated, and early diagnosis is essential: the goal of therapy is to reduce copper accumulation either by enhancing its urinary excretion or by decreasing its intestinal absorption. Medical therapies include penicillamine, trientine, zinc and tetrathiomolibdate. Liver transplantation is a relatively successful treatment option when medical therapy fails or in case of acute liver failure, even though it is also characterized by short- and long-term complications.

Brief report: no evidence for parvovirus B19 or hepatitis E virus as a cause of acute liver failure.

Viral hepatitis A and B are known to cause acute liver failure. While nearly 20% of acute liver failure cases are of indeterminate etiology, screening for other viruses has not been uniformly performed. We looked for evidence for parvovirus B19 and hepatitis E virus in sera from U.S. acute liver failure patients. For B19, 78 patients' sera, including 34 with indeterminate etiology, were evaluated by DNA dot-blot hybridization, reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay for immunoglobin G and M antibodies; none showed evidence for infection.

Sudden infant death syndrome: the colon connection.

The etiology of sudden infant death syndrome (SIDS) is not known. Various maternal and infant risk factors have been identified. Adoption of the non-prone position has reduced the incidence of SIDS but has not eliminated the problem. Some sulfate reducing bacteria in the colon produce hydrogen sulfide (H2S) which is as toxic as hydrogen cyanide. Normally, the colonic mechanism for metabolizing and detoxifying H2S is very effective and no H2S appears in the exhaled breath although small amounts are present in the flatus. We are putting forth the hypothesis that in some cases of SIDS colonocytic mechanism for detoxifying H2S may not have matured by the age of 3 months and H2S may be absorbed resulting in SIDS. The hypothesis can be tested by in vitro evaluation of colonic tissue from SIDS cases for its ability to detoxify H2S.

An adult case of acute lymphoblastic leukaemia presenting as hepatic dysfunction.

Acute hepatic dysfunction is a rare and often fatal presentation of haematological malignancies. We describe an adult case of acute lymphoblastic leukaemia presenting as an acute hepatitis. Due to the elevation in the patient's transaminases and bilirubin, standard acute lymphoblastic leukaemia induction therapy could not be used. Instead the combination of prednisone and asaparaginase were used to successfully induce remission.

Iron and manganese homeostasis in chronic liver disease: relationship to pallidal T1-weighted magnetic resonance signal hyperintensity.

The hyperintense signal in the globus pallidus of cirrhotic patients on T1-weighted magnetic resonance (MR) imaging has been postulated to arise from deposition of paramagnetic manganese2+ (Mn). Intestinal absorption of both iron and Mn are increased in iron deficiency; iron deficiency may therefore increase susceptibility to Mn neurotoxicity. To investigate the relationships between MR signal abnormalities and Mn and Fe status, 21 patients with chronic liver disease were enrolled (alcoholic liver disease, 5; primary biliary cirrhosis, 9; primary sclerosing cholangitis, 3; hepatitis B virus, 2; hepatitis C virus, 1; alpha1-antitrypsin deficiency, 1). Signal hyperintensity in the pallidum on axial T1 weighted images (repetition time/evolution time: 500 ms/15 ms) was observed in 13 of 21 subjects: four patients had mild hyperintensity, three moderate, and six exhibited marked hyperintensity. Erythrocyte Mn concentrations were positively correlated with the degree of the MR hyperintensity (Kendall's tau-b=0.52, P<0.005). The log of erythrocyte Mn concentration was also inversely correlated with all measures of iron status: hemoglobin (Pearson's R=-0.73, P<0.0005); hematocrit (R=-0.62, P<0.005); serum Fe concentrations (R=-0.65, P<0.005); and TIBC saturation (R=-0.62, P<0.005). These findings confirm the association of Mn with the development of pallidal hyperintensity in patients with liver disease. We further found that iron deficiency is an exacerbating factor, probably because of increased intestinal absorption of Mn. We therefore recommend that patients with chronic liver disease avoid Mn supplements without concurrent iron supplementation.

Reinfusion of concentrated ascitic fluid versus total paracentesis. A randomized prospective trial.

We compared the efficacy and safety of apheresis and reinfusion of concentrated ascites (ARCA) versus total paracentesis plus intravenous albumin (PARA) in a prospective trial on cirrhotic patients with tense ascites. Twenty-four patients were randomized to either ARCA (N = 12) or PARA (N = 12), and followed for two years. Sex, age, Child's class, and renal and liver function were similar in the two groups. The times the procedures were 2.7 +/- 1.0 (ARCA) vs 2.2 +/- 1.1 (PARA) hr, with removal of 8.8 +/- 3.5 (ARCA) and 6.9 +/- 3.4 (PARA) liters of ascites and intravenous infusion of 59.8 +/- 35.2 (ARCA) and 42.5 +/- 20.5 (PARA) g of albumin. Both procedures were safe. Biochemical signs of coagulative disturbances having no clinical relevance were observed after ARCA, with an increase in prothrombin time (P = 0.005) and serum FSP (P = 0.02). No significant changes in renal function, serum albumin, or plasma and urinary electrocytes were shown. Plasma renin activity increased after PARA (P = 0.02) and plasma atrial natriuretic factor increased after ARCA (P = 0.008), although no differences were observed in diuresis in the immediate follow-up. During the long-term follow-up, patient survival and recurrence of tense ascites were the same in both groups. We conclude that apheresis and reinfusion of concentrated ascites are as safe and effective as total paracentesis with albumin infusion for the treatment of tense ascites in cirrhotic patients.

[Neuroendocrine tumors and liver transplantation: review based on a case report]. / A neuroendocrin tumorok és a májátültetés: összefoglaló egy esettanulmány kapcsán.

A case of orthotopic liver transplantation (OLT) for secondary Neuroendocrine Tumor (NET), whose primary site was not detected at the time of surgery, is reported. The primary pancreatic lesion was found 20 months later in association with recurrence of neoplasm in the graft and with a paraneoplastic syndrome peculiar of glucagonoma. The patient started octreoide therapy with a decrease of the glucagone level but without reduction of the tumor size, nor disappearance of the clinical syndrome. A few months later the primary lesion was surgically removed, but her general condition deteriorated and the patient died waiting for liver retransplantation. A discussion about the management and the diagnostic tools for preoperative staging of these neoplasms and their ability to identify the primitive and secondary location of neuroendocrine tumors is presented.

Prognostic value of the galactose test in predicting survival of patients with cirrhosis evaluated for liver transplantation. A prospective multicenter Italian study. AISF Group for the Study of Liver Transplantation. Associazione Italiana per lo Studio del Fegato.

AIMS/METHODS: The present study aimed to examine whether the galactose elimination capacity can be used to predict the survival of patients with advanced liver disease. We studied 194 patients with cirrhosis, belonging to Child class B and C, for 2 years each. RESULTS: The overall probability of survival was 79% at 6 months, 72% at 1 year and 62% at 2 years. Variables significantly associated with the duration of survival, as assessed by univariate analysis, were the Child-Pugh score, presence of ascites, size of esophageal varices, prothrombin time, albumin, bilirubin, urea, creatinine, glucose and galactose elimination capacity. By a multivariable analysis, only Pugh score (p = 0.005), creatinine (p < 0.001), varices (p = 0.001) and galactose elimination capacity (p < 0.001) were independent predictors of mortality. The galactose elimination capacity was even more sensitive when the end-point was limited to deaths due to liver failure and hepatorenal syndrome. A new score obtained by summing the Pugh score with a score derived from galactose elimination capacity was quite simple and accurate for predicting survival. CONCLUSIONS: The quantitative measurement of liver function as the galactose elimination capacity could be of use to identify patients with cirrhosis and probable short survival who might benefit most from urgent transplantation.

Two cases of Kaposi's sarcoma in renal and liver transplant recipients treated with interferon.

We report two cases of Kaposi's sarcoma in recipients of solid organ transplants, presenting (Case 1) 12 months after liver transplantation and (Case 2) 7 months after kidney transplantation. Both patients share the following features: natives from the Mediterranean area (Southern Italy), multiple immunosuppressive regimen, infection with hepatitis B and cytomegalovirus. During the 3 yr of follow-up after the diagnosis, their immunosuppressive regimen was reduced and they were treated with alpha interferon with remission of the clinical findings. The management of Kaposi's sarcoma in organ transplant recipients remains a controversial issue because of the risks of organ rejection associated with the reduction of immunosuppression and with the use of interferon.

Treatment of ascites: old and new remedies.

Ascites is a common complication of chronic liver disease. Treatment of the underlying liver disease with modalities such as abstinence from alcohol in Laennec's cirrhosis, phlebotomy in hemochromatosis, copper removal in Wilson's disease, and steroids in autoimmune liver disease, can improve survival in many patients. In addition, therapy of ascites alleviates the symptoms and improves the quality of life of the patients, and probably decreases the incidence of life-threatening conditions including spontaneous bacterial peritonitis and hepatorenal syndrome. The mean survival rate at 2 years is approximately 50%. Precipitating factors such as gastrointestinal bleeding, nonsteroidal anti-inflammatory drugs and infections, should be identified, since most of them can be corrected. Most cirrhotics with ascites can be managed with a 'step-by-step' approach, including dietary salt restrictions, aldosterone antagonists, and loop diuretics. When tense or refractory ascites is present, large-volume paracentesis is safe and effective. Peritoneovenous shunting (i.e. Denver, LeVeen) is less frequently used because of perioperative morbidity and mortality, and thrombotic complications with occlusion of the stent. Reinfusion of concentrated ascites is of potential benefit and has been used in Europe. Transjugular intrahepatic portosystemic shunt (TIPS) is an alternative procedure performed by interventional radiologists that allows decompression of portal hypertension. In many cases, ascites is improved after TIPS, but long-term randomized trials for tense or refractory ascites comparing TIPS with standard therapy are not conclusive. Liver transplantation is the ultimate step for the treatment of ascites, providing the cure for the underlying liver disease as well. Transplantation is indicated when quality of life of the patient is impaired due to recurrent episodes of ascites, or in the presence of spontaneous bacterial peritonitis and hepatorenal syndrome.

Human natriuretic factor in cirrhotic patients undergoing orthotopic liver transplantation.

We measured the plasma levels of atrial natriuretic factor (ANF) during orthotopic liver transplantation (OLT) in eight adult patients with cirrhosis and ascites. The aim of this study was to determine whether significant differences in ANF concentration may be detected during the individual phases of OLT and to correlate these changes with hemodynamics. In each patient a hemodynamic assessment was achieved using a Swan-Ganz fiber optic catheter for continuous monitoring of cardiac output (CO), systemic vascular resistance index (SVRI), right filling pressure as assessed by central venous pressure (CVP), and left filling pressure by means of pulmonary arterial wedge pressure (PAWP). During reperfusion a clear-cut increase in ANF values was observed (P < 0.05). Concurrently, an increase in CVP (P < 0.05) and a decrease in SVRI were observed without any significant increase in diuresis. These data suggest that ANF might play a role in the development of the reperfusion syndrome.

Aprotinin efficacy on intraoperative bleeding and transfusion requirements in orthotopic liver transplantation.

BACKGROUND: Bleeding complications frequently occur during orthotopic liver transplantation (OLT), particularly in patients with liver cirrhosis. Enhanced fibrinolytic activity in plasma was seen to play a key role in the development of the hemostatic disorder and of hemorrhages. Aprotinin, a serine protease inhibitor, has been used in the prevention and/or treatment of hyperfibrinolytic states. STUDY DESIGN AND METHODS: In the present study, the effect of aprotinin on bleeding complications and transfusion requirements was investigated in OLT patients with liver cirrhosis. Seven consecutive cirrhotic patients undergoing OLT were infused with aprotinin following an original protocol (1,000,000-KIU intravenous loading dose plus 500,000 kallikrein-inhibitory units per hour until skin closure). Seven previous cirrhotic OLT patients not receiving aprotinin were used as controls. RESULTS: In the treated group, a significant decrease in the number of transfused units of packed red cells (48.7%, p < 0.01), fresh-frozen plasma (24.4%, p < 0.05), platelets (35.9%, p < 0.01), and autologous blood (55.2%, p < 0.01) was observed as compared with the control group. Moreover, the mean length of operation was significantly shorter in the aprotinin-infused patients than in untreated patients (8.3 +/- 1.2 vs. 10.1 +/- 1.8 hours, respectively; p < 0.01)). In the aprotinin-treated group, the antifibrinolytic efficacy was confirmed by the lack of increase in D-dimer levels and decrease of fibrinogen in plasma; on the contrary, these changes were always seen in the group not receiving aprotinin. CONCLUSION: Infusion of aprotinin during OLT in cirrhotic patients can be recommended for the prevention of hyperfibrinolysis-triggered bleeding, thus reducing transfusion requirements. A possible protective effect on the primary nonfunction of the grafted liver is suggested.

Sexuality of alcoholic postmenopausal women: effects of duration of alcohol abstinence.

Little is known about the sexuality of alcoholic postmenopausal women, and even less is known about the influence of abstinence on self-assessed measures of sexual function. We now report findings in 60 postmenopausal women to whom a standardized questionnaire was administered. The responses provided information related to not only perceptions of sexuality, but also sexual behavior and performance. Women were categorized as alcohol abstinent (AA) for > 1 year (long AA, n = 33) or < 1 year (short AA, n = 27). There were no differences between the groups in age, age at menarche, age at menopause, or age at onset of heavy drinking and alcohol dependence. The mean response rate to 12 sexuality-related questions was comparable in the long AA and short AA groups (83.8% and 85.6%, respectively), and reflected the prevalence of having a regular sexual partner (76% and 85%, respectively). There were statistical differences between the two groups with respect to sexual desire, arousability, and responsiveness during alcohol abstinence, but not during alcohol dependence. Further, there were significant differences with respect to measures of current sexuality: higher proportions of long AA women reported sex being important, as well as their sexual life and intercourse being satisfying. Taken together, these findings suggest that alcoholic postmenopausal women abstinent from alcohol for longer than 1 year report greater satisfaction with the sexual aspects of their lives than women abstinent for a shorter period of time.