Surveillance for hepatocellular carcinoma in patients with cirrhosis improves outcome.

OBJECTIVE: Liver transplantation has become an effective treatment for cirrhotic patients with early-stage hepatocellular carcinoma. We hypothesized that the quality of surveillance for hepatocellular carcinoma influences prognosis by affecting access to liver transplantation. METHODS: A total of 269 patients with cirrhosis and hepatocellular carcinoma were retrospectively categorized into 3 groups according to quality of surveillance: standard-of-care (n=172) (group 1); substandard surveillance (n=48) (group 2); and absence of surveillance in patients not recognized to be cirrhotic (n=59) (group 3). RESULTS: Three-year survival in the 60 patients who underwent liver transplantation was 81% versus 12% for patients who did not undergo transplantation (P<.001). The percentages of patients who underwent transplantation according to tumor stage at diagnosis (T1, T2, T3, and T4) were 58%, 35%, 10%, and 1%, respectively. Hepatocellular carcinoma was diagnosed at stages 1 and 2 in 70% of patients in group 1, 37% of patients in group 2, and only 18% of patients in group 3 (P <.001). Liver transplantation was performed in 32% of patients in group 1, 13% of patients in group 2, and 7% of patients in group 3 (P<.001). Three-year survival from cancer diagnosis in patients in group 3 (12%) was significantly worse than in patients in group 1 (39%) or group 2 (27%) (each P<.05). Eighty percent of patients in group 3 had subtle abnormalities of cirrhosis on routine laboratory tests. CONCLUSION: The quality of surveillance has a direct impact on hepatocellular carcinoma stage at diagnosis, access to liver transplantation, and survival.

Non-decompensated cirrhosis as a risk factor for invasive aspergillosis: a case report and review of the immune dysfunction of cirrhosis.

Invasive aspergillosis is a frequently insidious syndrome that carries a poor prognosis even when promptly and appropriately treated. Those patients that are identified as possessing risk factors for invasive aspergillosis are more likely to receive early therapy. Patients with profound immunosuppression, such as those with hematologic malignancy, iatrogenic immunosuppression for solid organ transplant, and advanced AIDS, are clearly at risk for invasive aspergillosis. Recently, invasive aspergillosis has been reported in patients with subtle immune dysfunction such as those with critical illness and advanced cirrhosis. However, patients with early cirrhosis also possess risk for invasive mycoses. We report a case of non-decompensated cirrhosis as the predisposition to invasive aspergillosis and review the immune dysfunction of cirrhosis that creates this risk.

Treatment of chronic hepatitis C virus in African Americans with genotypes 2 and 3.

Previous studies have documented that sustained virologic response (SVR) is significantly reduced in African Americans with chronic HCV genotype 1 following treatment with interferon and ribavirin when compared with Caucasians. The specific aim of the present retrospective study was to assess virologic response to interferon and ribavirin in African Americans with HCV genotypes 2 and 3. A review of our database identified 42 African Americans and 334 Caucasians with HCV genotypes 2 and 3. Patients coinfected with hepatitis B or human immunodeficiency virus, chronic renal failure, and recipients of an organ transplant were excluded. Thirty of the African Americans were treated with either standard interferon or peginterferon and ribavirin as initial treatment for chronic HCV. Ninety of the 334 Caucasians were matched to the African Americans with regards to genotype, cirrhosis, treatment regimen, sex, age, and body weight for comparison of virologic response. The proportion of patients with HCV genotype 2 was significantly greater (P < 0.001) in African Americans compared with Caucasians (81%vs 52%). End-of-treatment virologic response was observed in 94% of Caucasians compared with 80% in African Americans (P= 0.036). SVR was observed in 82% and 57% of Caucasians and African Americans, respectively (P= 0.012). Similar results were observed when patients who had been treated with only peginterferon and ribavirin were assessed. These results suggest that African Americans have a global defect in their ability to eradicate HCV infection following treatment with interferon and ribavirin which transcends across all genotypes.

MELD-XI: a rational approach to "sickest first" liver transplantation in cirrhotic patients requiring anticoagulant therapy.

Priority for "sickest first" liver transplantation (LT) in the United States is determined by the model for end-stage liver disease (MELD). MELD is a good predictor of short-term mortality in cirrhosis, but it can overestimate risk when international normalized ratio (INR) is artificially elevated by anticoagulation. An alternate prognostic index omitting INR is needed in this situation. We retrospectively analyzed survival data for 554 cirrhotic veterans referred for consideration of LT prior to December 1, 2003 (training group). Using logistic regression we derived a predictive formula for 90-day pretransplant mortality incorporating bilirubin and creatinine but omitting INR. We normalized this formula to the same scale as MELD using linear regression. This yielded MELD-XI (for MELD excluding INR) = 5.11 Ln(bilirubin) + 11.76 Ln(creatinine) + 9.44. Accuracy of MELD-XI was validated in a holdout group of 278 cirrhotic veterans referred after December 1, 2003, and in an independent validation dataset of 7,203 cirrhotic adults listed for LT in the United States between May 1, 2001, and October 31, 2001. MELD-XI and MELD correlated well in training, holdout, and independent validation cohorts (r = 0.930, 0.954, and 0.902, respectively). In the holdout cohort, c-statistics of MELD vs. MELD-XI for mortality were, respectively, 0.939 vs. 0.906 at 30 days;0.860 vs. 0.841 at 60 days; 0.842 vs. 0.829 at 90 days; and 0.795 vs. 0.797 at 180 days. In the independent validation dataset, c-statistics for MELD vs. MELD-XI as predictors of 90-day survival were, respectively, 0.857 vs. 0.843 in noncholestatic liver diseases and 0.905 vs. 0.894 in cholestatic liver diseases. Comparable MELD and MELD-XI scores were associated with comparable prognosis. In conclusion, MELD-XI, despite omission of INR, is nearly as accurate as MELD in predicting short-term survival in cirrhosis. In patients treated with oral anticoagulants, substitution of MELD-XI for MELD may permit more accurate assessment of risk and more rational assignment of "sickest first" priority for LT.

Cholestatic liver disease. Recognizing the clinical signs.

Cholestatic liver disease in women is most often seen as primary biliary cirrhosis, an autoimmune disease that may take many years to cause symptoms and is often a challenge for physicians to identify. Primary sclerosing cholangitis is a cholestatic liver disease with a more straightforward presentation. Most commonly seen in men, this disease may rapidly progress to cirrhosis or to a third common cholestatic disease, cholangiocarcinoma. In this article, Drs Bhatia and Mihas discuss the etiologic and diagnostic features of these entities and explore medical, surgical, and palliative treatment approaches. In all three diseases, liver transplantation is a viable, life-extending therapeutic option.

Safety of an immune-enhancing nutrition supplement in cirrhotic patients with history of encephalopathy.

Malnutrition in advanced cirrhosis may worsen liver function and increase susceptibility to infections. Immune-enhancing nutrition supplements (IENS) may be of value, but their safety in patients with decompensated cirrhosis and history of encephalopathy is unknown. We assessed the safety of Impact Recover (Novartis, St. Louis Park, MN), an orally palatable IENS, in 12 men with hepatic cirrhosis of Child-Turcotte-Pugh (CTP) class B or C, ages 40-60. On day 0, patients were evaluated serially for 6 hours after ingestion of 2 packets of Impact Recover. Despite a transient doubling of the blood ammonia, no cognitive abnormalities were noted on clinical assessment or psychometric testing. Subsequently, patients were instructed to ingest 3 packets per day of Impact Recover for 56 days, after which supplements were stopped. Patients were evaluated in a fasting state on days 0 (baseline), 56 (end of treatment), and 112 (follow-up). One patient was transplanted on day 21, and another died after an urgent cholecystectomy on day 30. The remaining 10 patients completed the study. Mean value of CTP score was 9 (range, 7-11) and mean value of model for end-stage liver disease (MELD) score was 14 (7-21), and there was no change after 8 weeks of IENS. Only 1 experienced transient worsening of encephalopathy after omitting lactulose. Performances on psychometric tests did not change. Transferrin levels increased rapidly with IENS, then returned toward baseline after IENS was stopped. Fasting insulin and peptide YY (PYY) levels also increased, but fasting glucose and hemoglobin A1C did not change. Trends in other nutrition and immune parameters did not reach significance. We conclude that acute and chronic administration of Impact Recover was well tolerated in cirrhotic patients with controlled encephalopathy. Further studies are justified to assess potential efficacy of long-term IENS in preventing infection and slowing progression in advanced cirrhosis.

Celiac disease: current concepts in diagnosis and treatment.

Celiac disease is a complex autoimmune enteropathy that affects the small bowel in genetically predisposed individuals. It is thought that celiac disease is the result of an inappropriate T cell-mediated immune response against ingested gluten protein. The characteristic lesion of the small intestinal mucosa includes loss of absorptive villi and infiltration of the lamina propria with inflammatory cells. The clinical presentation of celiac disease varies greatly depending on patient's age, duration and extent of the disease, and the presence of extraintestinal manifestations. Unfortunately, most patients with celiac disease have either silent or atypical presentations, thus escaping diagnosis for several years. Medical nutrition therapy with lifelong adherence to a strict gluten-free diet is the only accepted treatment of celiac disease. Individuals at risk for this entity should undergo appropriate serologic testing, but there is no evidence to support mass screening.

High-density lipoprotein cholesterol as an indicator of liver function and prognosis in noncholestatic cirrhotics.

BACKGROUND AND AIMS: The liver plays a central role in production and degradation of lipoproteins. Declining lipoprotein cholesterol may reflect deteriorating liver function. METHODS: We reviewed the records of 248 veterans with noncholestatic cirrhosis followed in our clinics or referred for liver transplantation between January 1, 1997 and October 31, 2002 (analysis period) and confirmed our findings prospectively in 165 noncholestatic cirrhotic veterans newly referred for liver transplantation between November 1, 2002 and May 1, 2004 (validation period). RESULTS: In the analysis group, albumin, bilirubin, INR, and Model for End-Stage Liver Disease (MELD) score correlated strongly with high-density lipoprotein (HDL) cholesterol, weakly but significantly with total cholesterol and very-low-density lipoprotein cholesterol (VLDL), and poorly with low-density lipoprotein cholesterol (LDL). Transplant-free mortality at 90, 180, and 365 days was 17/201 (8.5%), 19/173 (11.0%), and 38/119 (31.9%), respectively. Death at all 3 time points was associated with significantly lower initial levels of HDL, VLDL, and total cholesterol, but not LDL cholesterol. Of the lipoproteins, HDL was the best predictor of survival at 180 and 365 days (concordance statistics .86+/-.05 and .78+/-.05, respectively). By multivariate logistic regression, HDL cholesterol and MELD score were independent predictors of survival at 6 and 12 months. By Cox regression, HDL cholesterol below 30 mg/dL was associated with 3.4-fold increase in the hazard ratio for cirrhotic death. In the validation period, HDL cholesterol was confirmed to be significantly associated with death or transplantation at 6 or 12 months. CONCLUSIONS: HDL cholesterol in noncholestatic cirrhotic patients is a liver function test and an indicator of prognosis.

Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death.

Despite the adoption of "sickest first" liver transplantation, pretransplant death remains common, and many early deaths occur despite initially low Model for End-stage Liver Disease (MELD) scores. From 1997-2003, we studied 507 cirrhotic United States veterans referred for consideration of liver transplantation to identify additional predictors of early mortality. Most of the patients were male (98%) with cirrhosis caused by hepatitis C and/or alcohol (88%). Data for 296 patients referred prior to February 27, 2002 (training group), were analyzed; findings were validated in 211 patients referred subsequently (validation group). In the training group, 61 patients (21%) died within 180 days without transplantation; their median initial MELD score was 21. MELD score, persistent ascites, and low serum sodium (<135 meq/L) were independent predictors of early mortality. In patients with a MELD score of less than 21, only low serum sodium and persistent ascites were independent predictors of mortality; for MELD scores above 21, only MELD was independently predictive. Prognostic significance of persistent ascites and low serum sodium for low MELD score patients was confirmed in the validation group. Risk varied continuously with worsening hyponatremia. Modifying MELD, by including points for persistent ascites and low serum sodium, improved prediction of early pretransplant mortality in low MELD score patients. In conclusion, persistent ascites and low serum sodium identify patients with cirrhosis with high mortality risk despite low MELD scores. Ascites, hyponatremia, and other findings indicative of hemodynamic decompensation merit further prospective study as prognostic indicators in patients awaiting liver transplantation, and should be considered in setting minimal listing criteria.

Marginal Zone B-cell Lymphoma (MALT Lymphoma).

The preferred terminology for mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach (variously referred to as MALT lymphoma, MALToma, low-grade MALToma, or pseudolymphoma) is marginal zone B-cell lymphoma (MZBL). MZBL, the hallmark of which is the lymphoepithelial lesion, develops as a consequence of Helicobacter pylori infection in susceptible individuals. In general, MZBL is slow growing, can remain localized for years, and has an excellent prognosis. Staging involves endoscopy with biopsy, computed tomography scanning, and endoscopic ultrasound. In patients with limited disease, eradication of H. pylori leads to remission. In patients who fail eradication therapy or have more extensive disease, surgery, chemotherapy, and radiation alone and in various combinations have been used successfully.

Hepatic hydrothorax: pathophysiology, diagnosis, and management.

Hepatic hydrothorax occurs in approximately 5 to 12% of patients with cirrhosis and portal hypertension. Various therapeutic modalities ranging from dietary and pharmacologic interventions to surgical approaches are available for the management of this condition. Treatment must be individualized based on the patient's response to conservative management as well as the severity of the underlying liver disease. Hepatic hydrothorax may be complicated by spontaneous bacterial empyema, which portends a poor prognosis with a mortality rate of up to 20%. All patients with hepatic hydrothorax should be evaluated for possible liver transplantation.

Zollinger-Ellison Syndrome.

Zollinger-Ellison syndrome (ZES) is caused by a gastrin-producing tumor called a gastrinoma, which results in gastric acid hypersecretion. Gastrin stimulates the parietal cell to secrete acid directly and indirectly by releasing histamine from enterochromaffin-like (ECL) cells, and induces hyperplasia of parietal and ECL cells. ZES should be suspected in patients with severe erosive or ulcerative esophagitis, multiple peptic ulcers, peptic ulcers in unusual locations, refractory peptic ulcers, complicated peptic ulcers, peptic ulcers associated with diarrhea, and a family history of multiple endocrine neoplasia type 1 (MEN-1) or any of the endocrinopathies associated with MEN-1. The initial diagnostic test for ZES should be a fasting serum gastrin level when antisecretory medications are discontinued. If the gastrin level is elevated, gastric acidity should be assessed through pH or gastric analysis. It should be noted that hypochlorhydria causes feedback stimulation of antral gastrin secretion. In suspected cases of ZES with mild hypergastrinemia, the secretin stimulation test may be useful. Initial treatment for ZES should be oral high-dose proton pump inhibitors. If parenteral therapy is needed, intermittent bolus injection of pantoprazole is recommended. Total gastrectomy and antisecretory surgery is rarely required. Somatostatin receptor scintigraphy (SRS) is the initial localization study of choice. Endoscopic ultrasound (EUS) may have a similar sensitivity for identifying primary tumors. A combination of SRS and EUS detects greater than 90% of gastrinomas. In patients without metastasis and without MEN-1, surgical cure is possible in 30%. It has been suggested that patients with gastrinomas larger than 2.5 cm, irrespective of whether they have MEN-1, should undergo surgical resection in an effort to decrease the risk for metastasis.

Fructose diphosphate attenuates the acetaminophen-induced liver injury in the rat evidence for involvement of nitric oxide.

We have previously shown that fructose-1,6-diphosphate (FDP) stimulates the synthesis of nitric oxide probably by stimulating the hepatic inducible nitric oxide synthase (iNOS). The aim of the present study was to evaluate the hepatoprotective role of FDP in acetaminophen-induced liver injury and whether this hepatoprotective effect is mediated by nitric oxide. Liver injury was induced in adult Sprague-Dawley rats by the administration of acetaminophen (1.6 g/kg by gavage) 10 min prior to the intraperitoneal injection of either FDP or normal saline. Liver injury was assessed by alanine aminotransferase (ALT) activity in the serum. iNOS and malondialdehyde (MDA) levels were determined in liver homogenates. Acetaminophen produced striking elevations of serum ALT, high MDA levels and a profound decrease in the liver iNOS. Administration of FDP attenuated the ALT and MDA elevations and prevented the liver iNOS depletion caused by acetaminophen. Pretreatment of the animals with the iNOS inhibitor L-NAME abolished this hepatoprotection. These findings suggest that FDP protects against acetaminophen-induced liver injury, at least partly, by stimulating production of nitric oxide.

Mikulicz syndrome associated with a malignant large cell gastric lymphoma: a case report and review of the literature.

There is much confusion in the literature regarding the differences between Mikulicz disease and Mikulicz syndrome. This may be because there seems to be a connection between the disease and disease processes associated with the syndrome. This article provides historical data discussing the emergence of Mikulicz disease, confusions regarding its definition, and finally offers an explanation to the interrelationships of these two entities. This case report hypothesizes that the non-Hodgkin's lymphoma (NHL), which in association with Sjögren's syndrome and Mikulicz disease in this patient comprised the Mikulicz syndrome, may have transformed into his malignant large-cell gastric lymphoma. It supports conclusions in the literature that Mikulicz disease, benign lymphoepithelial lesion, and Sjögren's syndrome may all be a part of the same disease process as graduated variants of one another, with malignant lymphoma being a recognized complication of these entities.

Alcoholic hepatitis.

Preview Liver damage due to alcohol abuse is a severe condition often leading to cirrhosis or death. Unfortunately, the exact mechanisms involved are not well understood, and traditional treatment options have had limited success in improving morbidity and mortality rates. The authors of this article review recent studies on pathogenesis and discuss the pros and cons of current medical and surgical management.