As a more consultative but less procedurally oriented specialty, Hepatology has been considered a financial liability in some academic centers. However, no actual data exist on the relative contribution of a Hepatology practice. The purpose of this study was to evaluate the direct and indirect (i.e., downstream effect) charges generated by a Hepatology section in comparison with a Gastroenterology section. Using a computerized database, retrospective cohorts of new outpatient consultations and initial admissions seen by the Hepatology and Gastroenterology sections over a 3-month period were created. The cohorts were followed for 12 months. Charges generated directly to the section (direct charges) and to the hospital system (indirect charges) were calculated. Each cohort consisted of 179 patients. The Hepatology patients generated 5,851,463 dollars in overall charges for the hospital, compared with 2,273,339 dollars for the Gastroenterology cohort. Only 3.6% of the Hepatology charges were direct, compared with 15.9% of the Gastroenterology charges. For every 1 dollar billed by Hepatology, the hospital system generated an additional 26.95 dollars in charges (51.03 dollars for the orthotopic liver transplantation patients, and 14.26 dollars for the non-orthotopic liver transplantation patients). For every 1 dollar billed by Gastroenterology, the hospital system generated an additional 5.31 dollars in charges. Similar inpatient collection rates were seen between the two groups (27.7% for hepatology and 33.6% for gastroenterology). In conclusion, although Hepatology generates only a small amount of direct charges, it accounts for a very substantial amount of indirect or downstream billing for an academic medical center. This study validates the importance of a hospital's support for a Hepatology section, especially in a center performing orthotopic liver transplantation.
Purpose: A 21-year-old man with no past medical history was admitted to the medical intensive care unit with hypotension and hypoxia. The patient denied any gastrointestinal bleeding or abdominal pain. Family history was unremarkable for colon or liver disease. He was eventually felt to have sepsis and acute respiratory distress syndrome. Lab data revealed a hemoglobin of 8.5, with a mean corpuscular volume of 65 and ferritin of 16. His liver function tests (LFTs) were mildly elevated on admission; however, on hospital day four, his aspartate aminotransferase rose to 374, alanine aminotransferase rose to 228, and alkaline phosphatase rose to 311. The patient had received ethacrynic acid earlier in his hospital course, and the elevated LFTs were attributed to this medication as well as sepsis. Ethacrynic acid was stopped, and the LFTs improved. As part of the workup for the elevated LFTs, a liver ultrasound was performed, which revealed a right hepatic mass measuring 7.3 cm. Magnetic resonance imaging demonstrated a 6-cm subcapsular mass in the right hepatic lobe with at least two satellite nodules. Biopsy of the mass revealed moderately differentiated adenocarcinoma, intestinal type. Given this cancer and the patient's anemia, colonoscopy was performed, which revealed a partially obstructing tumor in the proximal rectum (Figure 1), as well as innumerable polyps ranging from three to 20 mm throughout the colon (Figure 2). The endoscopic findings were concerning for familial adenomatous polyposis (FAP). Pathology from the rectal mass revealed invasive, moderately differentiated adenocarcinoma. Pathology from the larger polyps revealed tubulovillous adenomas, while biopsies of several of the smaller polyps revealed tubular adenomas. An esophagogastroduodenoscopy was performed, demonstrating multiple gastric polyps. Pathology was notable for fundic gland polyps. The patient was started on a chemotherapeutic regimen composed of folinic acid, fluorouracil, and oxaliplatin (FOLFOX), underwent preoperative radiation therapy, and eventual total proctocolectomy with loop ileostomy and liver resection, and continues his chemotherapy with the plan to complete a total of 12 cycles. This case demonstrates several important teaching points. First, in a young male patient who presents with severe iron-deficiency anemia, even in the absence of gastrointestinal symptoms, a thorough investigation of the gastrointestinal tract is necessary. Second, the absence of a positive family history does not rule out the possibility of FAP. Finally, a simple non-invasive test, such as an ultrasound, should be considered in all patients who present with elevated LFTs.
This guideline has been approved by the American Association for the Study of Liver Diseases and the American College of Gastroenterology and represents the position of both associations. These recommendations provide a data-supported approach to the management of patients with varices and variceal hemorrhage. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic (Medline search); (2) several consensus conferences among experts; (3) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines1; (4) guideline policies, including the American Association for the Study of Liver Diseases' Policy Statement on Development and Use of Practice Guidelines and the American Gastroenterological Association's Policy Statement on the Use of Medical Practice Guidelines2; and (5) the authors' years of experience caring for patients with cirrhosis and varices. Intended for use by healthcare providers, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. As with other practice guidelines, this guideline is not intended to replace clinical judgment but rather to provide general guidelines applicable to the majority of patients. They are intended to be flexible, in contrast to standards of care, which are inflexible policies designed to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a class (reflecting benefit versus risk) and level (assessing strength or certainty) of evidence to be assigned and reported with each recommendation (Table 1, adapted from the American College of Cardiology and the American Heart Association Practice Guidelines3, 4). When little or no data exist from well-designed prospective trials, emphasis is given to results from large series and reports from recognized experts. Further controlled clinical studies are needed to clarify aspects of this statement, and revision may be necessary as new data appear. Clinical considerations may justify a course of action that differs from these recommendations. These recommendations are fully endorsed by the American Association for the Study of Liver Diseases and the American College of Gastroenterology. Portal hypertension is a progressive complication of cirrhosis. Therefore, the management of the patient with cirrhosis and portal hypertensive gastrointestinal bleeding depends on the phase of portal hypertension at which the patient is situated, from the patient with cirrhosis and portal hypertension who has not yet developed varices to the patient with acute variceal hemorrhage for whom the objective is to control the active episode and prevent rebleeding. Practice guidelines for the diagnosis and treatment of gastroesophageal variceal hemorrhage, endorsed by the American Association for the Study of Liver Diseases (AASLD), American College of Gastroenterology (ACG), American Gastroenterological Association (AGA), and American Society of Gastrointestinal Endoscopy (ASGE), were published in 1997.5 Since then, a number of randomized controlled trials have advanced our approach to managing variceal hemorrhage. Three international consensus conferences have been held (Baveno III in 2000, Baveno IV in 2005, and an AASLD/EASL single topic conference in 2007) in which experts in the field have evaluated the changes that have occurred in our understanding of the pathophysiology and management of gastroesophageal hemorrhage.6, 7 In this updated practice guideline we have reviewed the randomized controlled trials and meta-analyses published in the last decade and have incorporated recommendations made by consensus. Cirrhosis, the end stage of any chronic liver disease, can lead to portal hypertension. Portal pressure increases initially as a consequence of an increased resistance to flow mostly due to an architectural distortion of the liver secondary to fibrous tissue and regenerative nodules. In addition to this structural resistance to blood flow, there is an active intrahepatic vasoconstriction that accounts for 20%-30% of the increased intrahepatic resistance,8 and that is mostly due to a decrease in the endogenous production of nitric oxide.9, 10 Portal hypertension leads to the formation of porto-systemic collaterals. However, portal hypertension persists despite the development of these collaterals for 2 reasons: (1) an increase in portal venous inflow that results from splanchnic arteriolar vasodilatation occurring concomitant with the formation of collaterals11; and (2) insufficient portal decompression through collaterals as these have a higher resistance than that of the normal liver.12 Therefore, an increased portal pressure gradient results from both an increase in resistance to portal flow (intrahepatic and collateral) and an increase in portal blood inflow. The preferred, albeit indirect, method for assessing portal pressure is the wedged hepatic venous pressure (WHVP) measurement, which is obtained by placing a catheter in the hepatic vein and wedging it into a small branch or, better still, by inflating a balloon and occluding a larger branch of the hepatic vein. The WHVP has been shown to correlate very closely with portal pressure both in alcoholic and non-alcoholic cirrhosis.13 The WHVP is always corrected for increases in intraabdominal pressure (e.g., ascites) by subtracting the free hepatic vein pressure (FHVP) or the intraabdominal inferior vena cava pressure, which act as internal zeroes. The resultant pressure is the hepatic venous pressure gradient (HVPG), which is best accomplished with the use of a balloon catheter, usually taking triplicate readings and, when measured with a proper technique, is very reproducible and reliable.14 Since it is a measure of sinusoidal pressure, the HVPG will be elevated in intrahepatic causes of portal hypertension, such as cirrhosis, but will be normal in prehepatic causes of portal hypertension, such as portal vein thrombosis. The normal HVPG is 3-5 mmHg. The HVPG and changes in HVPG that occur over time have predictive value for the development of esophagogastric varices,15, 16 the risk of variceal hemorrhage,17-19 the development of non-variceal complications of portal hypertension,17, 20, 21 and death.19, 21-23 Single measurements are useful in the prognosis of both compensated and decompensated cirrhosis, while repeat measurements are useful to monitor response to pharmacological therapy and progression of liver disease. Limitations to the generalized use of HVPG measurement are the lack of local expertise and poor adherence to guidelines that will ensure reliable and reproducible measurements,14 as well as its invasive nature. Gastroesophageal varices are the most relevant porto-systemic collaterals because their rupture results in variceal hemorrhage, the most common lethal complication of cirrhosis. Varices and variceal hemorrhage are the complications of cirrhosis that result most directly from portal hypertension. Patients with cirrhosis and gastroesophageal varices have an HVPG of at least 10-12 mm Hg.15, 24 Gastroesophageal varices are present in approximately 50% of patients with cirrhosis. Their presence correlates with the severity of liver disease (Table 2); while only 40% of Child A patients have varices, they are present in 85% of Child C patients.25 Patients with primary biliary cirrhosis may develop varices and variceal hemorrhage early in the course of the disease even in the absence of established cirrhosis.26 It has also been shown that 16% of patients with hepatitis C and bridging fibrosis have esophageal varices.27 Patients without varices develop them at a rate of 8% per year,16, 28 and the strongest predictor for development of varices in those with cirrhosis who have no varices at the time of initial endoscopic screening is an HVPG >10 mmHg.16 Patients with small varices develop large varices at a rate of 8% per year. Decompensated cirrhosis (Child B/C), alcoholic cirrhosis, and presence of red wale marks (defined as longitudinal dilated venules resembling whip marks on the variceal surface) at the time of baseline endoscopy are the main factors associated with the progression from small to large varices.28 Variceal hemorrhage occurs at a yearly rate of 5%-15%, and the most important predictor of hemorrhage is the size of varices, with the highest risk of first hemorrhage (15% per year) occurring in patients with large varices.29 Other predictors of hemorrhage are decompensated cirrhosis (Child B/C) and the endoscopic presence of red wale marks.29 Although bleeding from esophageal varices ceases spontaneously in up to 40% of patients, and despite improvements in therapy over the last decade, it is associated with a mortality of at least 20% at 6 weeks.30-32 Patients with an HVPG >20 mmHg (measured within 24 hours of variceal hemorrhage) have been identified as being at a higher risk for early rebleeding (recurrent bleeding within the first week of admission) or failure to control bleeding (83% vs. 29%) and a higher 1-year mortality (64% vs. 20%) compared to those with lower pressure.33, 34 Late rebleeding occurs in approximately 60% of untreated patients, mostly within 1-2 years of the index hemorrhage.35, 36 Variceal wall tension is probably the main factor that determines variceal rupture. Vessel diameter is one of the determinants of variceal tension. At an equal pressure, a large diameter vessel will rupture while a small diameter vessel will not rupture.37 Besides vessel diameter, one of the determinants of variceal wall tension is the pressure within the varix, which is directly related to the HVPG. Therefore, a reduction in HVPG should lead to a decrease in variceal wall tension, thereby decreasing the risk of rupture. Indeed, variceal hemorrhage does not occur when the HVPG is reduced to <12 mmHg.17, 20 It has also been shown that the risk of rebleeding decreases significantly with reductions in HVPG greater than 20% from baseline.18 Patients whose HVPG decreases to <12 mmHg or at least 20% from baseline levels ("HVPG responders") not only have a lower probability of developing recurrent variceal hemorrhage,36 but also have a lower risk of developing ascites, spontaneous bacterial peritonitis, and death.21 Gastric varices are less prevalent than esophageal varices and are present in 5%-33% of patients with portal hypertension with a reported incidence of bleeding of about 25% in 2 years, with a higher bleeding incidence for fundal varices.38 Risk factors for gastric variceal hemorrhage include the size of fundal varices (large>medium>small, defined as >10 mm, 5-10 mm, and <5 mm, respectively), Child class (C>B>A), and endoscopic presence of variceal red spots (defined as localized reddish mucosal area or spots on the mucosal surface of a varix).39 Gastric varices are commonly classified based on their relationship with esophageal varices as well as their location in the stomach.38 Gastroesophageal varices (GOV) are an extension of esophageal varices and are categorized into 2 types. The most common are Type 1 (GOV1) varices, which extend along the lesser curvature. They are considered extensions of esophageal varices and should be managed similarly. Type 2 (GOV2) gastric varices extend along the fundus and tend to be longer and more tortuous. Isolated gastric varices (IGV) occur in the absence of esophageal varices and are also classified into 2 types. Type 1 (IGV1) are located in the fundus and tend to be tortuous and complex, and type 2 (IVG2) are located in the body, antrum, or around the pylorus. The presence of IGV1 fundal varices requires excluding the presence of splenic vein thrombosis. The gold standard in the diagnosis of varices is esophagogastroduodenoscopy (EGD). In a consensus meeting it was recommended that the size classification be as simple as possible, i.e., in 2 grades (small and large),40 either by semiquantitative morphological assessment or by quantitative size with a suggested cut-off diameter of 5 mm, with large varices being those greater than 5 mm. When varices are classified in 3 sizes—small, medium, or large—as occurs in most centers by a semiquantitative morphological assessment (with small varices generally defined as minimally elevated veins above the esophageal mucosal surface, medium varices defined as tortuous veins occupying less than one-third of the esophageal lumen, and large varices defined as those occupying more than one-third of the esophageal lumen), recommendations for medium-sized varices are the same as for large varices,29 because this is how they were grouped in prophylactic trials. As shown below, nonselective β-blockers prevent bleeding in more than half of patients with medium or large varices. Therefore, it is recommended that patients with cirrhosis undergo endoscopic screening for varices at the time of diagnosis.41, 42 Since the point prevalence of medium/large varices is approximately 15%-25%,25 the majority of subjects undergoing screening EGD either do not have varices or have varices that do not require prophylactic therapy. There is, therefore, considerable interest in developing models to predict the presence of high-risk varices by non-endoscopic methods. Several studies have evaluated possible noninvasive markers of esophageal varices in patients with cirrhosis, such as the platelet count, Fibrotest, spleen size, portal vein diameter, and transient elastography.43, 44 However, the predictive accuracy of such noninvasive markers is still unsatisfactory, and until large prospective studies of noninvasive markers are performed, endoscopic screening is still the main means of assessing for the presence of esophageal varices.43 Cost-effective analyses using Markov models have suggested either empiric β-blocker therapy for all patients with cirrhosis45 or screening endoscopy for patients with compensated cirrhosis, and universal β-blocker therapy without screening EGD for patients with decompensated cirrhosis.46 Neither of these strategies considers a recent trial showing that β-blockers do not prevent the development of varices and are associated with significant side effects,16 nor do they consider endoscopic variceal ligation as an alternative prophylactic therapy. Until prospective studies validate these approaches, screening EGD is still the recommended approach. The frequency of surveillance endoscopies in patients with no or small varices depends on their natural history. EGD should be performed once the diagnosis of cirrhosis is established.6, 41 In patients with compensated cirrhosis who have no varices on screening endoscopy, the EGD should be repeated in 2-3 years.6 In those who have small varices, the EGD should be repeated in 1-2 years.6 In the presence of decompensated cirrhosis, EGD should be repeated at yearly intervals.41, 42 EGD is expensive and usually requires sedation. It can be avoided in patients with cirrhosis who are already on nonselective β-blockers for other reasons (e.g., arterial hypertension. In those on a selective β-blocker (metoprolol, atenolol) for other reasons, switching to a nonselective β-blocker (propranolol, nadolol) would be necessary. A procedure that may replace EGD is esophageal capsule endoscopy. Two recent pilot studies show that capsule endoscopy is a safe and well-tolerated way to diagnose esophageal varices,47, 48 although its sensitivity remains to be established. Thus, capsule endoscopy may play a future role in screening for esophageal varices if additional larger studies support its use. EGD also remains the main method for diagnosing variceal hemorrhage.7, 41 The diagnosis of variceal hemorrhage is made when diagnostic endoscopy shows one of the following: active bleeding from a varix, a "white nipple" overlying a varix, clots overlying a varix, or varices with no other potential source of bleeding.40 Screening esophagogastroduodenoscopy (EGD) for the diagnosis of esophageal and gastric varices is recommended when the diagnosis of cirrhosis is made (Class IIa, Level C). On EGD, esophageal varices should be graded as small or large (>5 mm) with the latter classification encompassing medium-sized varices when 3 grades are used (small, medium, large). The presence or absence of red signs (red wale marks or red spots) on varices should be noted (Class IIa, Level C). Rationale for the management of varices Current therapies for the management of varices/variceal hemorrhage and their effect on portal venous inflow, portal resistance, and portal pressure are summarized in Table 3. Pharmacological therapy consists of splanchnic vasoconstrictors (vasopressin and analogues, somatostatin and analogues, nonselective β-blockers) and venodilators (nitrates). Vasoconstrictors act by producing splanchnic vasoconstriction and reducing portal venous inflow. Venodilators theoretically act by decreasing intrahepatic and/or portocollateral resistance. However, all available venodilators (e.g., isosorbide mononitrate) have a systemic hypotensive effect and the decrease in portal pressure appears to be more related to hypotension (i.e., a decrease in flow) rather than a decrease in resistance.49 The combination of a vasoconstrictor and a vasodilator has a synergistic portal pressure-reducing effect.50, 51 Endoscopic therapies, such as sclerotherapy or endoscopic variceal ligation (EVL), are local therapies that have no effect on either portal flow or resistance. Shunting therapy, either radiological (transjugular intrahepatic portosystemic shunt) or surgical, by bypassing the site of increased resistance, markedly reduces portal pressure by bypassing the site of increased resistance. A large multicenter, placebo-controlled, double-blinded trial failed to show a benefit of nonselective β-blockers (timolol) in the prevention of varices in patients with cirrhosis who had portal hypertension at baseline (HVPG >5 mmHg) but had not yet developed varices.16 The study did show, however, that patients who achieved even a mild reduction in HVPG after 1 year of therapy (≥10% from baseline) had a significantly lower development of varices, and that a larger percentage of patients on timolol showed this reduction in HVPG compared to those on placebo. A significantly larger number of patients with moderate or severe adverse events were observed in the timolol group (48%) compared to the placebo group (32%). Serious symptomatic adverse events occurred in 20 patients (18%) in the timolol group and in 6 patients (6%) in the placebo group. These results do not support the suggested universal use of β-blockers in cirrhosis.45 Given the natural history of varices, expert consensus panels have determined that surveillance endoscopies should be performed every 2-3 years in these patients, and annually in the setting of decompensation.6, 42 In patients with cirrhosis who do not have varices, nonselective β-blockers cannot be recommended to prevent their development (Class III, Level B). In patients who have compensated cirrhosis and no varices on the initial EGD, it should be repeated in 3 years (Class I, Level C). If there is evidence of hepatic decompensation, EGD should be done at that time and repeated annually (Class I, Level C). A meta-analysis of trials evaluating nonselective β-blockers (i.e., propranolol, nadolol) in the prevention of first variceal hemorrhage (primary prophylaxis) analyzed the results of 3 trials that included patients with small varices.35 In this meta-analysis, the incidence of first variceal hemorrhage was quite low (7% over 2 years), and although it was reduced with β -blockers (2% over 2 years), this reduction was not statistically significant. Two studies have investigated the efficacy of nonselective β-blockers in preventing the enlargement of small varices, with contradictory results. In the first study,52 the 2-year proportion of patients with large varices was unexpectedly larger in the propranolol group compared to the placebo group (31% vs. 14%). However, the study enrolled patients with no and small varices and over a third of the patients were lost to follow-up. Another large multicenter, placebo-controlled, but single-blinded trial, showed that patients with small varices treated with nadolol had a significantly slower progression to large varices (11% at 3 years) than patients who were randomized to placebo (37% at 3 years), with no differences in survival.53 The risk of variceal bleeding was lower in patients who started treatment with β-blockers when varices were small (12% at 5 years) compared with patients who started β-blockers once large varices were observed (22% at 5 years). However, this benefit was related to the longer time patients remained in a condition of low-risk (i.e., small) varices, given that once large varices developed and all patients were treated with β-blockers, the risk of bleeding was very similar.53 Similar to other studies, a higher percentage of patients on β-blockers had to be withdrawn from the study because of adverse events (11%) compared to patients on placebo (1%). Prophylaxis with β-blockers should be used in patients with small varices who are at a high risk for bleeding; that is, those with advanced liver disease and the presence of red wale marks on varices.7 Other patients with small varices can receive β-blockers to prevent variceal growth, although their long-term benefit has not been well established. In those who choose not to take β-blockers, expert consensus panels have determined that surveillance endoscopies should be performed every 2 years, and annually in the setting of decompensation.6, 42 In patients with cirrhosis and small varices that have not bled but have criteria for increased risk of hemorrhage (Child B/C or presence of red wale marks on varices), nonselective β-blockers should be used for the prevention of first variceal hemorrhage (Class IIa, Level C). In patients with cirrhosis and small varices that have not bled and have no criteria for increased risk of bleeding, β-blockers can be used, although their long-term benefit has not been established (Class III, Level B). In patients with small varices that have not bled and who are not receiving β-blockers, EGD should be repeated in 2 years (Class I, Level C). If there is evidence of hepatic decompensation, EGD should be done at that time and repeated annually (Class I, Level C). In patients with small varices who receive β-blockers, a follow-up EGD is not necessary. A meta-analysis of 11 trials that included 1,189 patients evaluating nonselective β-blockers (i.e., propranolol, nadolol) versus non-active treatment or placebo in the prevention of first variceal hemorrhage shows that the risk of first variceal bleeding in patients with large- or medium-sized varices is significantly reduced by β-blockers (30% in controls vs. 14% in β-blocker-treated patients),35 and indicates that 1 bleeding episode is avoided for every 10 patients treated with β-blockers. Mortality is also lower in the β-blocker group compared with the control group and this difference has recently been shown to be statistically significant.54 Additionally, a cost-effectiveness study comparing nonselective β-blockers, sclerotherapy, and shunt surgery shows that β-blockers were the only cost-effective form of prophylactic therapy.55 Nonselective β-blockers (propranolol, nadolol) reduce portal pressure by decreasing cardiac output (β-1 effect) and, more importantly, by producing splanchnic vasoconstriction (β-2 effect), thereby reducing portal blood flow. Selective β-blockers (atenolol, metoprolol) are less effective and are suboptimal for primary prophylaxis of variceal hemorrhage. A decrease in HVPG <12 mmHg essentially eliminates the risk of hemorrhage and improves survival,17 while reductions >20% from baseline56 or even >10% from baseline57 significantly decrease the risk of first variceal hemorrhage. In the majority of the published studies, the dose of β-blockers was titrated to decrease the heart rate 25% from baseline. However, since HVPG measurement is not widely available and a reduction in heart rate does not correlate with reduction in HVPG,58 the dose of nonselective β-blockers (propranolol, nadolol) is adjusted to maximal tolerated doses. Propranolol is usually started at a dose of 20 milligrams (mg) twice a day (BID). Nadolol is is usually started at a dose of 40 mg once a day (QD). Because a randomized trial showed that the risk of bleeding recurs when treatment with β-blockers is stopped,59 prophylactic therapy should be continued indefinitely. Approximately 15% of patients from trials have relative contraindications to the use of β-blockers, such as asthma, insulin-dependent diabetes (with episodes of hypoglycemia), and peripheral vascular disease.60 The most common side effects related to β-blockers in cirrhosis are lightheadedness, fatigue, and shortness of breath. Although some of these side effects disappear with time or after dose reduction, treatment withdrawal occurs in 15% of patients. Trials in which nadolol was used have reported lower rates of side effects (≈10%) than those involving propranolol (≈17%)60; however, direct comparisons have not been performed. Endoscopic variceal ligation (EVL) has been compared to β-blockers in several randomized trials in patients with high-risk varices (large varices with or without red wale markings). Two recent meta-analyses of these trials have been performed: the first included 8 trials and comprised 596 subjects (285 with EVL, 311 with β-blockers)61; and the second included 12 studies comprising 839 subjects (410 with EVL, 429 with β-blockers).62 Both showed that EVL is associated with a small but significant lower incidence of first variceal hemorrhage without differences in mortality. The results are the same when only fully published trials or high-quality trials are analyzed. Although the EVL group has a significantly lower rate of adverse events (4% vs. 13%), the EVL events are more severe and include bleeding from ligation-induced esophageal ulcers in 10 patients (with 2 fatal outcomes) and overtube-induced esophageal perforation in 1 patient. This last complication is currently less likely to occur given the use of multi-band ligation devices that minimize the use of overtubes for band placement. In the β-blocker group, severe adverse events necessitating withdrawal (hypotension, fatigue, shortness of breath) resolved after discontinuation of the medication, although 10 patients bled on withdrawal of β-blockers (with 2 fatal outcomes). One of the more recent studies included in these meta-analyses had to be stopped before the planned number of patients was enrolled and after a mean follow-up of only 18 months, because interim analysis showed a significantly higher number of treatment "failures" (bleeding or a severe side effect) in the propranolol group compared to the EVL group (6 vs. 0).63 The unfortunate premature discontinuation of this trial is discussed in recent editorials that argue that bleeding rates were not significantly different between groups, and that only one "failure" in the EVL group would have rendered the differences non-significant.64, 65 In contrast, the 2 largest randomized trials66, 67 and a more recent trial,68 not included in the above cited meta-analyses, have shown that EVL is equivalent to nadolol66 or to propranolol67, 68 in preventing the first variceal hemorrhage. After careful review of the available data, a recent consensus panel of experts concluded that both nonselective β-blockers and EVL are effective in preventing first variceal hemorrhage and therefore the decision should be based on patient characteristics and preferences, local resources and expertise. Therapies not recommended for primary prophylaxis The combination of a nonselective β-blocker and isosorbide mononitrate (ISMN) has a synergistic portal pressure-reducing effect and could theoretically be more effective than β-blockers alone in preventing first variceal hemorrhage.51 In fact, a non-blinded trial comparing nadolol alone with nadolol plus ISMN demonstrated a significantly lower rate of first hemorrhage in the group treated with combination therapy.69 These results were maintained after 55 months of follow-up, without differences in survival.70 However, 2 more recent larger double-blinded, placebo-controlled trials were unable to confirm these favorable results,71, 72 and a greater number of side effects were noted in the combination therapy group.71 Therefore, the use of a combination of a β-blocker and ISMN cannot be recommended currently for primary prophylaxis until there is further proof of efficacy. The combination of a nonselective β-blocker and spironolactone (which has been shown to lower portal pressure by reducing plasma volume and splanchnic blood flow) has been recently examined in a preliminary double-blind, placebo-controlled trial.73 The results suggest that the addition of spironolactone does not increase the efficacy of nadolol in the prophylaxis of first variceal hemorrhage. The role of combination of a nonselective β-blocker and EVL in the prevention of first variceal hemorrhage was recently evaluated in a randomized but not placebo-controlled trial performed in patients with and without cirrhosis who had high-risk varices.74 There were no differences in the incidence of bleeding or death between groups, and even though varices recurred more frequently in the EVL alone group, side effects were more common in the EVL + propranolol group. Given the lack of differences in the primary outcomes, combination therapy cannot be currently recommended. ISMN alone was shown in one study to be as effective as propranolol in preventing first variceal hemorrhage.75
A 63 year-old black woman was referred for hepatitis C, genotype 1a. She denied any alcohol or drug use. She has a history of end-stage diabetic nephropathy and underwent deceased donor kidney-pancreas transplant in 2003. The kidney failed and she returned to dialysis. Her pancreas function was stable and she had never had issues with pancreatitis or pancreatic rejection. She was chronically maintained on tacrolimus and mycophenolate. She was started on hepatitis C therapy with Elbasvir and Grazoprevir and ribavirin (due to the presence of an NS5A resistance mutation). Two weeks into hepatitis C therapy, she presented with significant epigastric pain, nausea, and vomiting. Physical examination revealed epigastric tenderness without peritoneal signs. Initial labs revealed lipase of 29,232 U/L (upper limit of normal 393 U/L), normal LFT's, and a FK506 trough of 7.6 ng/mL. Abdominal CT revealed peripancreatic fat stranding of both the native and transplanted pancreas. The patient's hepatitis C antiviral regimen was discontinued. Lipase levels initially improved but then began to rise. MRI of the pancreas with and without contrast revealed fat stranding and trace amount of free fluid around the transplanted pancreas, and no narrowing of the transplanted pancreatic duct. The native pancreas was atrophic without evidence of pancreatitis. Due to worsening of the lipase levels, a biopsy of the transplanted pancreas was performed which revealed mild interlobular active inflammation consistent with acute rejection, grade one. Immunostain C4d was negative suggesting cellular etiology of rejection. The patient was treated with methylprednisolone and four doses of thymoglobulin. The lipase improved, her nausea resolved and she was able to tolerate a normal diet. Overall, this case is very concerning for pancreatic transplant rejection due to the hepatitis C antiviral medications. This would be the first such case report. Ribavirin has previously been associated with pancreatitis, but not induction of pancreatic transplant rejection. Elbasvir and/or Grazoprevir have never been studied in this patient population. Caution should be used in treating hepatitis C patients with the new antiviral agents in the setting of prior pancreatic transplant. Monitoring serial lipase levels may be reasonable, especially if the patient develops any gastrointestinal symptoms.
Inflammatory pseudotumor (IPT) of the liver is a rare inflammatory process often mistaken for hepatic malignancy. We report a case of a patient with IPT who presented with fever, mental status changes, and a hepatic mass who was successfully treated with a right hepatectomy. A 67 year old Asian female presented with 2 weeks of fever and confusion. Laboratory evaluation revealed alkaline phosphatase 233 U/L, total bilirubin 2.2 mg/dL, AST 80 U/L, ALT 113 U/L, WBC 17 × 109 cells/L. An MRI revealed an 8.6 × 6.2 cm cystic mass in the right lobe of the liver. A mammogram, EGD, and colonoscopy were unremarkable. FNA of the mass revealed acute inflammatory cells and benign hepatocytes. The patient was transferred to our hospital on empiric antibiotics. Laboratory evaluation revealed albumin 2.3 g/dL, alkaline phosphatase 501 U/L, total bilirubin 0.8 mg/dL, AST 39 U/L, ALT 23 U/L, AFP 2.8 ng/mL, CEA 2.8 ng/mL. Serologic testing for chronic liver disease was negative. A CT scan revealed a 10.4 × 6.8 cm heterogeneous mass in the right lobe with multiple areas of necrosis and pneumobilia suggestive of a necrotic tumor. The patient was taken for a right hepatectomy and an 8 × 7.5 cm cystic yellow-tan hepatic mass was found (Figure). Histology showed multiple microabscesses surrounded by reactive and xanthomatous histiocytes (CD68+, S100−) with hemorrhage and focal cholangitis consistent with IPT. No malignant cells, viral inclusions, or parasites were seen and special stains for fungi and AFB were negative. The patient was discharged 9 days after the hepatectomy and has been doing well more than 6 months later. IPT should be considered when patients present with clinical and radiological features mimicking malignant neoplasm. IPT is often mistaken radiologically for hepatocellular carcinoma, cholangiocarcinoma, or metastatic tumor. Directed biopsy may nondiagnostic. The diagnosis can often only be made after complete surgical resection. Hence, surgical resection is definitive for both diagnosis and treatment.[figure1]Figure
6-Thioguanine (6-TG), the active metabolite of 6-mercaptopurine and its prodrug azathioprine, are thought to be responsible for clinical efficacy in the treatment of active Crohn's disease. Its use as a therapeutic agent for inflammatory bowel disease (IBD) has been limited to patients who are resistant to or intolerant of other antimetabolites. Short-term experience with this agent has not demonstrated an increased incidence of hematologic or hepatic toxicity; however long-term safety data are scarce. We herein report a patient who developed acute sinusoidal obstruction syndrome after 14 months of successful thioguanine treatment. This is the first report of such a complication in an adult treated with 6-TG for active Crohn's disease.
s Submitted for the 68th Annual Scientific Meeting of the American College of Gastroenterology October 10-15, 2003, Baltimore, Maryland: CLINICAL VIGNETTES: PDF Only
The Task Force on Medical Care of the Vietnamese Child under the auspices of the American Academy of Pediatrics should be commended on the breadth and speed of the reporting. It is unfortunate that the terse statements required of the committee do not allow for an airing of controversy, as exemplified by the conclusion that γ-globulin for household contacts of patients with hepatitis B "is of no value."1 This long-established view was largely predicated on studies of individuals exposed to serum hepatitis by multiple transfusion, where the results2,3 may reflect the dose of γ-globulin used, the hepatitis B antibody (anti-HB8) titer, the large quantity of virus in the transfusion, or the variety types of hepatitis (A, B, C, drug, or postoperative) studied together as post-transfusion hepatitis.
