Shannan R. Tujios

Mechanisms of drug-induced liver injury: from bedside to bench.

The low incidence of idiosyncratic drug-induced liver injury (DILI), together with the lack of a reliable diagnostic biomarker and robust preclinical and in vitro toxicology test systems for the condition have limited our ability to define the mechanisms of DILI. A notable exception is acetaminophen hepatotoxicity, which is associated with the formation of a well-characterized and highly reactive intermediate metabolite, N-acetyl-p-benzoquinone imine. However, studies have also suggested a role for the host immune response and variation in the expression of the lymphocyte CD44 gene in the pathogenesis of acetaminophen hepatotoxicity. A careful review of the laboratory, clinical and histological phenotype of patients with DILI can provide potential clues to the mechanisms of disease pathogenesis, as observed with fialuridine and valproate hepatotoxicity. In addition, the use of transcriptomic and genomic approaches in patients with well-characterized DILI has provided important insights into the involvement of the host immune response in the pathogenesis of hepatotoxicity associated with the administration of flucloxacillin, lumiracoxib or ximelagatran. This Review highlights new developments regarding the potential role of reactive metabolites, mitochondrial toxicity, host immune-response pathways and biliary transporters in the etiopathogenesis of DILI. Going forward, a bedside-to-bench approach could improve our understanding of the mechanisms and risk factors for DILI.

Update in the management of chronic hepatitis B.

Purpose of review To review the recent developments in the management of chronic hepatitis B (CHB) based on the articles published between January 2012 and January 2013. Recent findings International guidelines have been updated to include recent discoveries in the natural history of CHB, how to determine who should be treated, recommendations of management of special populations, and support of highly potent medications with high genetic barrier to resistance as the first-line therapy. Sustained response rates to interferon may be influenced by the IL28B genotype and can be predicted by on-treatment monitoring of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA. Long-term viral suppression can be obtained by entecavir and tenofovir even in cases of multidrug resistance, leading to decreased rates of hepatocellular carcinoma and death. Summary Current therapies suppress, but rarely eradicate hepatitis B. Drug resistance remains a barrier to success in the long-term treatment of CHB, especially in resource-poor areas and in previously treated patients. Quantitative hepatitis B surface antigen in addition to other clinical data may provide personalized treatment decisions based on risk and response. There remains a need for novel therapies targeting HBV replication and immune system for CHB cure.

Perceived and Actual Quality of Life With Ulcerative Colitis: A Comparison of Medically and Surgically Treated Patients

OBJECTIVES:Patients with chronic ulcerative colitis (UC) often refuse colectomy, despite data indicating that it might improve quality of life. We hypothesized that perceived utility values are different for patients living with UC compared with UC patients after total proctocolectomy. Our aims were to compare the perceived utility assigned by UC patients with and without a colectomy to standardized chronic UC and post-colectomy scenarios, and to compare the utility of actual health states among groups.METHODS:We surveyed patients in a tertiary referral center from three groups, including non-UC, UC patients without colectomy, and UC patients who were post-colectomy. We measured the Time-Trade-Off (TTO) utilities of subjects for standardized scenarios, describing moderate UC and a post-colectomy state. Among all UC patients (with and without colectomy), we measured TTO utility for their own health state.RESULTS:Responses were obtained from 150 patients per group (n=450). The non-UC patients considered UC and colectomy scenarios equally (0.92), which was similar to UC patients without colectomy (0.90 and 0.91). Post-colectomy patients strongly preferred the colectomy scenario to the UC scenario (0.86 vs. 0.92, P<0.001). The median utility of UC patients without colectomy for their actual health state was higher than that of post-colectomy patients (0.96 and 0.92, P<0.05). Patients with more social support were more likely to have undergone colectomy compared with patients with little social support (odds ratio=1.20 per dependent/supporter).CONCLUSIONS:Patients living with UC prefer their actual health state to a perceived UC scenario or a post-colectomy scenario. Patients who have undergone colectomy equate the quality of life in their actual state with that in a post-colectomy scenario, and prefer each to a perceived chronic UC state. Given the variety of preferences and the importance of social support, opportunities to interact with UC patients who have previously undergone colectomy could help patients living with UC and their physicians to navigate these complex choices.

New advances in chronic hepatitis B.

Purpose of review This article reviews recent developments in the evaluation and treatment of chronic hepatitis B (CHB) based on articles published between December 2010 and January 2012. Recent findings The majority of patients infected with CHB have not been diagnosed and most at-risk individuals have not been immunized. Progression to cirrhosis depends on hepatitis B virus (HBV) genotype, hepatitis B e antigen (HBeAg) presence, persistently high levels of HBV DNA, and elevated alanine aminotransferase, although hepatitis B surface antigen (HBsAg) kinetics may help predict natural history and antiviral response. Antiviral resistance limits the success of nucleos(t)ide analogs and agents such as entecavir and tenofovir with high potency and high genetic barrier to resistance are considered first-line therapy. Specialized treatment of CHB in pregnancy, coinfection, decompensated cirrhosis, and posttransplant is safe and effective. Summary The complications of CHB can now be avoided and reversed with potent antiviral suppression of HBV DNA. For now, treatment is long-term and further studies are needed to discern whether sequential or combination therapy may be superior to current monotherapy for certain patients. Increased awareness should improve screening resulting in more frequent treatment and immunization of at-risk individuals toward eventual CHB eradication.

Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure

Hyperammonemia has been associated with intracranial hypertension and mortality in patients with acute liver failure (ALF). We evaluated the effect of renal replacement therapy (RRT) on serum ammonia level and outcomes in ALF. This was a multicenter cohort study of consecutive ALF patients from the United States ALF Study Group registry between January 1998 and December 2016. First, we studied the association of ammonia with hepatic encephalopathy (HE) and 21‐day transplant‐free survival (TFS; n = 1,186). Second, we studied the effect of RRT on ammonia for the first 3 days post study admission (n = 340) and on 21‐day TFS (n = 1,186). Higher admission (n = 1,186) median ammonia level was associated with grade 3‐4 HE (116 vs. 83 μmol/L) and mortality at day 21 attributed to neurological (181 vs. 90 μmol/L) and all causes (114 vs. 83 μmol/L; P < 0.001 for all). Among 340 patients with serial ammonia levels, 61 (18%) were on continuous RRT (CRRT), 59 (17%) were on intermittent RRT (IRRT), and 220 (65%) received no RRT for the first 2 days. From days 1 to 3, median ammonia decreased by 38%, 23%, and 19% with CRRT, IRRT, and no RRT, respectively. Comparing to no RRT use, whereas ammonia reduction with CRRT was significant (P = 0.007), with IRRT it was not (P = 0.75). After adjusting for year of enrollment, age, etiology, and disease severity, whereas CRRT (odds ratio [OR], 0.47 [95% confidence interval {CI}, 0.26‐0.82]) was associated with reduction in 21‐day transplant‐free all‐cause mortality, IRRT (OR, 1.68 [95% CI, 1.04‐2.72]) was associated with an increase. Conclusion: In a large cohort of ALF patients, hyperammonemia was associated with high‐grade HE and worse 21‐day TFS. CRRT was associated with a reduction in serum ammonia level and improvement of 21‐day TFS. (Hepatology 2018;67:711‐720).

Transpapillary Gallbladder Stents Can Stabilize or Improve Decompensated Cirrhosis in Patients Awaiting Liver Transplantation

Goals: To describe the short-term and long-term outcomes in 34 consecutive decompensated cirrhotic patients with symptomatic gallbladder disease undergoing transpapillary gallbladder stent (TGS) placement. Background: Endoscopic TGS placement is a minimally invasive means of treating symptomatic gallbladder disease in poor surgical candidates. Study: Between June 2005 and June 2011, 34 patients with cirrhosis and symptomatic gallbladder disease underwent attempted TGS placement. Results: Median patient age was 52 years, 56% were hospitalized, and 48% were listed for liver transplantation. The median model for end-stage liver disease (MELD) score was 15 (range, 6 to 40) and 88% were Child-Turcotte-Pugh class B/C. A double pigtailed stent was successfully placed in 94% of the patients. At 1-month follow-up, clinical improvement was noted in 82% of the treated subjects and the MELD scores in 14 of 22 (64%) evaluable subjects improved or stabilized. Actuarial transplant-free survival was 53% in the liver transplant candidates with a mean follow-up of 352 days, whereas survival was 44% in the 18 nontransplant candidates with a mean follow-up of 1.5 years. Periprocedural complications included pancreatitis in 5 patients, cholangitis in 3, and 1 patient with cystic duct perforation. In addition, 2 subjects had symptomatic bleeding from traumatic duodenal ulcerations 2 years after TGS placement that necessitated stent removal. Conclusions: Endoscopic TGS placement was technically feasible in 94% of decompensated cirrhotics and was associated with a relatively low rate of periprocedural (26%) and long-term complications (6%). Stabilization or improvement in clinical status and MELD scores was seen in the majority of treated patients.

Acute liver failure induced by idiosyncratic reaction to drugs: Challenges in diagnosis and therapy

Acute liver failure (ALF) requires urgent attention to identify etiology and determine prognosis, in order to assess likelihood of survival or need for transplantation. Identifying idiosyncratic drug‐induced liver injury (iDILI) may be particularly difficult, but the illness generally follows a subacute course, allowing time to assess outcome and find a liver graft if needed. Not all drugs that cause iDILI lead to ALF; the most common are antibiotics including anti‐tuberculous medications, non‐steroidal anti‐inflammatory agents and herbal and dietary supplements (HDS). Determining causality remains challenging particularly if altered mentation is present; identifying the causative agent depends in part on knowing the propensity of the drugs that have been taken in the proper time interval, plus excluding other causes. In general, iDILI that reaches the threshold of ALF will more often than not require transplantation, since survival without transplant is around 25%. Treatment consists of withdrawal of the presumed offending medication, consideration of N‐acetylcysteine (NAC), as well as intensive care. Corticosteroids have not proven useful except perhaps in instances of apparent autoimmune hepatitis caused by a limited number of agents. Recently developed prognostic scoring systems may also aid in predicting outcome in this setting.

What’s in a name? The heterogeneous clinical spectrum and prognostic factors in a cohort of adults with hemophagocytic lymphohistiocytosis

PURPOSE Hemophagocytic lymphohistiocytosis (HLH) in adults is rare but frequently fatal. Diagnosis is often delayed and treatment approaches vary significantly in contrast to the protocol-driven approach typically used in pediatric HLH. To improve care of these complex patients, this study retrospectively examined the prevalence, clinical characteristics, therapies and outcomes of adult HLH patients at two large tertiary care centers. METHODS Adult patients with HLH confirmed by retrospective review of electronic medical records using HLH2004 criteria during admissions to the University of Texas Southwestern and Parkland Memorial Hospitals between June 2007 and June 2017 were studied. RESULTS Of 31 patients included, 67.7% were male with mean age of 46 years. Average time from admission to diagnosis was 10.5 days. 48% of patients had malignancy, with T-cell lymphoma being most common. Infections were seen in 70%. Autoimmune disorders were found in 9.6%. In total, 13 patients survived (44.8%). Median survival was 8 months with increased mortality in malignancy-associated HLH (median 0.56 months versus 36.5 months, p < 0.001). T-cell lymphoma carried a worse prognosis than other malignancies. Central nervous system disease, hypoalbuminemia, elevated bilirubin, elevated soluble interleukin 2 receptor, and elevated lactate dehydrogenase, were also associated with poor survival. Treatment varied significantly. No individual treatment improved survival. CONCLUSION This study corroborates prior limited data in adult HLH patients regarding poor survival, particularly in malignancy-associated HLH. Earlier recognition of this disease and a multidisciplinary approach to streamline diagnosis and optimize treatment are needed to improve outcomes in adult HLH patients.

CON (“The window is closed”): In patients with cirrhosis with ascites, the clinical risks of nonselective beta‐blocker outweigh the benefits and should NOT be prescribed

Even though nonselective beta-blockers (NSBBs) have proven benefits in cirrhosis, some evidence suggests they may be harmful in a subset of patients with decompensated cirrhosis, in particular those with refractory ascites, baseline hypotension, or at high risk for infection. The decision to initiate a NSBB should be individualized; continuation of NSBB should be continually reassessed in decompensated patients with ascites. Consider decreasing or stopping the NSBB in patients with low mean arterial pressure (<80 mm Hg), hyponatremia, renal insufficiency, ongoing infection, or refractory ascites requiring frequent paracentesis.

Reply to: “Should venous ammonia be used in decision making acute liver failure patients?”

1) Cardoso FS, Gottfried M, Tujios S, Olson JC, Karvellas CJ; US Acute Liver Failure Study Group. Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure. HEPATOLOGY 2018;67:711-720. 2) Ong JP, Aggarwal A, Krieger D, Easley KA, Karafa MT, Van Lente F, et al. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med 2003;114:188193. 3) Stahl J. Studies of the blood ammonia in liver disease. Its diagnostic, prognostic, and therapeutic significance. Ann Intern Med 1963;58:1-24. 4) Clemmesen JO, Kondrup J, Ott P. Splanchnic and leg exchange of amino acids and ammonia in acute liver failure. Gastroenterology 2000;118:1131-1139. 5) Manjunath R, Nagesh H, Bhardwaj V. Clinical correlation between arterial versus venous ammonia levels in hepatic encephalopathy in cirrhosis of liver. Journal of Evolution of Medical and Dental Sciences 2014;19:5322-5332.