Michael R. Charlton

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

These recommendations are based on the following: (1) a formal review and analysis of the recently published world literature on the topic [Medline search up to June 2011]; (2) the American College of Physicians’ Manual for Assessing Health Practices and Designing Practice Guidelines; (3) guideline policies of the three societies approving this document; and (4) the experience of the authors and independent reviewers with regards to NAFLD. Intended for use by physicians and allied health professionals, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible and adjustable for individual patients. Specific recommendations are evidence-based wherever possible, and when such evidence is not available or inconsistent, recommendations are made based on the consensus opinion of the authors. To best characterize the evidence cited in support of the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1). The strength of recommendations in the GRADE system is classified as strong (1) or weak (2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (A), moderate (B) or low-quality (C). This is a practice guideline for clinicians rather than a review article and interested readers can refer to several comprehensive reviews published recently.

The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology

The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology NAGA CHALASANI, MD, FACG,* ZOBAIR YOUNOSSI, MD, FACG, JOEL E. LAVINE, MD, PhD, ANNA MAE DIEHL, MD, ELIZABETH M. BRUNT, MD, KENNETH CUSI, MD, MICHAEL CHARLTON, MD,** and ARUN J. SANYAL, MD

Frequency and Outcomes of Liver Transplantation for Nonalcoholic Steatohepatitis in the United States

BACKGROUND & AIMS The relative frequency of nonalcoholic steatohepatitis (NASH) as an indication for liver transplantation and comparative outcomes following transplantation are poorly understood. METHODS We analyzed the Scientific Registry of Transplant Recipients for primary adult liver transplant recipients from 2001 to 2009. RESULTS From 2001 to 2009, 35,781 patients underwent a primary liver transplant, including 1959 for who NASH was the primary or secondary indication. The percentage of patients undergoing a liver transplant for NASH increased from 1.2% in 2001 to 9.7% in 2009. NASH is now the third most common indication for liver transplantation in the United States. No other indication for liver transplantation increased in frequency during the study period. Compared with other indications for liver transplantation, recipients with NASH are older (58.5±8.0 vs 53.0±8.9 years; P<.001), have a larger body mass index (>30 kg/m2) (63% vs 32%; P<.001), are more likely to be female (47% vs 29%; P<.001), and have a lower frequency of hepatocellular carcinoma (12% vs 19%; P<.001). Survival at 1 and 3 years after liver transplantation for NASH was 84% and 78%, respectively, compared with 87% and 78% for other indications (P=.67). Patient and graft survival for liver recipients with NASH were similar to values for other indications after adjusting for level of creatinine, sex, age, and body mass index. CONCLUSIONS NASH is the third most common indication for liver transplantation in the United States and is on a trajectory to become the most common. Outcomes for patients undergoing a liver transplant for NASH are similar to those for other indications.

Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis

BACKGROUND As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase. METHODS We conducted a phase 3, open-label study involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir-velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin. CONCLUSIONS Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. (Funded by Gilead Sciences; ASTRAL-4 ClinicalTrials.gov number, NCT02201901.).

Evolution of Causes and Risk Factors for Mortality Post-Liver Transplant: Results of the NIDDK Long-Term Follow-Up Study

Although mortality rates following liver transplantation (LT) are well described, there is a lack of detailed, prospective studies determining patterns of and risk factors for long‐term mortality. We analyzed the multicenter, prospectively obtained The National Institute of Diabetes and Digestive and Kidney Diseases LT Database of 798 transplant recipients from 1990 to 1994 (follow‐up 2003). Overall, 327 recipients died. Causes of death >1 year: 28% hepatic, 22% malignancy, 11% cardiovascular, 9% infection, 6% renal failure. Renal‐related death increased dramatically over time. Risk factors for death >1 year (univariate): male gender, age/decade, pre‐LT diabetes, post‐LT diabetes, post‐LT hypertension, post‐LT renal insufficiency, retransplantation >1 year, pre‐LT malignancy, alcoholic disease (ALD) and metabolic liver disease, with similar risks noted for death >5 years. Hepatitis C, retransplantation, post‐LT diabetes, hypertension and renal insufficiency were significant risk factors for liver‐related death. Cardiac deaths associated with age, male gender, ALD, cryptogenic disease, pre‐LT hypertension and post‐LT renal insufficiency. In summary, the leading causes of late deaths after transplant were graft failure, malignancy, cardiovascular disease and renal failure. Older age, diabetes and renal insufficiency identified patients at highest risk of poor survival overall. Diligent management of modifiable post‐LT factors including diabetes, hypertension and renal insufficiency may impact long‐term mortality.

A PROSPECTIVE ANALYSIS OF 1,930 PATIENTS WITH HEMATURIA TO EVALUATE CURRENT DIAGNOSTIC PRACTICE

PURPOSE The commonly accepted diagnostic algorithm for hematuria includes excretory urography (IVP) and cystoscopy. Some have suggested that ultrasound of the upper urinary tract is adequate and that cystoscopy is not necessary in younger patients with microscopic hematuria. We ascertain whether a less intensive algorithm could be adopted while retaining diagnostic efficacy. MATERIALS AND METHODS A total of 1,930 patients were enrolled prospectively in the study at a hematuria clinic between October 1994 and March 1997. Evaluation consisted of basic demographics, history and examination, routine blood tests, urinalysis and cytology. All patients underwent plain abdominal radiography, renal ultrasound, IVP and flexible cystoscopy. RESULTS A total of 1,194 males and 736 females with a mean age of 58 years (range 17 to 96) were included in the study. Overall, 61% of patients had no basis found for hematuria, 12% had bladder cancer, 13% had urinary tract infection and 2% had stones. Kidney and upper tract tumors were noted in 14 patients (0.7%), including 4 who presented with microscopic hematuria. If only ultrasound or IVP had been performed 4 of these cases would have been missed. Of 982 patients presenting with microscopic hematuria 51 had cancer. Bladder cancer was found in 7 patients younger than 40 years. CONCLUSIONS Our findings suggest that cystoscopy cannot be safely avoided even in younger patients with microscopic hematuria. Only a combination of ultrasound and IVP detected all upper tract tumors.

Nonalcoholic fatty liver disease: A review of current understanding and future impact

Nonalcoholic fatty liver disease (NAFLD), already the most common form of liver disease in the United States, can be expected to increase in prevalence and severity in parallel with national epidemics of obesity and type 2 diabetes. NAFLD is frequently associated with insulin resistance. While insulin resistance, and thereby hyperinsulinemia, are, in large part, metabolic consequences of obesity, the basis of diversity in severity and progression of inflammation and fibrosis is not known. Increased susceptibility to oxidative stress is likely to play a role. Several patient characteristics have been associated with more severe histological findings in patients with NAFLD, including type 2 diabetes, hypertension, age over 40 years, and higher transaminases. Liver biopsy is, however, required to accurately grade and stage NAFLD histologically. Although the natural history of NAFLD is relatively poorly defined, NAFLD is increasingly recognized as an important cause of decompensated liver disease. Weight reduction and improved insulin sensitivity are associated with improved biochemical and histological parameters of NAFLD. There are, however, no proven safe and efficacious pharmacological treatments for NAFLD.

Sofosbuvir and Ribavirin for Treatment of Compensated Recurrent Hepatitis C Virus Infection After Liver Transplantation

BACKGROUND & AIMS Interferon alfa-based regimens used to treat recurrent hepatitis C virus (HCV) infection after liver transplantation are poorly tolerated, associated with generally modest efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an interferon-free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 24 weeks in treating post-transplantation HCV infection. METHODS In a prospective, multicenter, open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any genotype after a primary or secondary liver transplantation. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values. The primary end point was sustained virologic response 12 weeks after treatment. RESULTS Of the 40 patients enrolled and treated, 78% were male, 85% were white, 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. Sustained virologic response 12 weeks after treatment was achieved by 28 of 40 patients (70%; 90% confidence interval: 56%-82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment. The most common adverse events were fatigue (30%), diarrhea (28%), and headache (25%). In addition, 20% of the subjects experienced anemia. Two patients discontinued study treatment because of adverse events, which were considered unrelated to study treatment. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported. CONCLUSIONS Sofosbuvir and ribavirin combination therapy for 24 weeks is an effective and well-tolerated interferon-free treatment for post-transplantation HCV infection. EudraCT, Number: 2012-002417-19; ClinicalTrials.gov, Number: NCT01687270.

Interleukin‐28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection

Polymorphism in the interleukin‐28B (IL28B) gene region, encoding interferon (IFN)‐λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty‐five patients received IFN‐based antiviral therapy. The CC IL28B variant was less common in the chronic HCV‐infected recipients than in non‐HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi‐square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D‐non‐CC/R‐non‐CC = 3/19 [16%] versus D‐CC/R‐non‐CC = 11/22 [50%] versus D‐non‐CC/R‐CC = 5/12 [42%] versus R‐CC/D‐CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver‐related). Conclusion: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN‐based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection. (Hepatology 2011;)

Risk Factors for and Clinical Course of Non‐Anastomotic Biliary Strictures After Liver Transplantation

Non‐anastomotic biliary stricture (NAS) formation is a major complication of liver transplantation. We prospectively determined the time to development of responsiveness to treatment, and clinical outcomes following NAS formation. In addition, an extensive analysis of the association of recipient, donor, and clinical variables with NAS formation was performed. A total of 749 consecutive patients was studied in a prospective, protocol‐based fashion. Seventy‐two patients (9.6%) developed NAS at a mean of 23.6 ± 34.2 weeks post‐transplantation. Non‐anastomotic biliary stricture formation resolved in only 6% of affected patients. Although patient survival was not affected, retransplantation and graft loss rates were significantly greater in recipients who developed NAS. In contrast to previous reports, a pretransplant diagnosis of HCV was associated with a low frequency of NAS formation. The incidence of NAS was independently associated with pretransplant diagnoses of PSC and autoimmune hepatitis. Hepatic artery thrombosis, and prolonged warm and cold ischemia times were also independent risk factors for NAS formation. We conclude that NAS developed in ∼10% of primary liver transplant recipients. A pretransplant diagnosis of autoimmune hepatitis has been identified as a novel independent risk factor for NAS formation. Development of NAS significantly attenuates graft but not patient survival.