Kapil B. Chopra

Nonalcoholic Fatty Liver Disease: A Clinical Review

Nonalcoholic fatty liver disease may be the most common liver disease in the United States, with a high prevalence in the obese, type 2 diabetic population, and it is probably underestimated as a cause for cirrhosis. Clinicopathologically, it represents a wide spectrum of histologic abnormalities and clinical outcomes, ranging from benign hepatic steatosis to cirrhosis. Pathophysiologically, insulin resistance is thought to be pivotal in the development of steatosis, after which a second oxidative stressor produces lipid peroxidation and nonalcoholic steatohepatitis (NASH). Liver biopsy is the gold standard for diagnosis and prognosis. The need for an effective treatment is both clear and urgent, yet in the absence of proven therapies, treatment is directed toward weight loss and comorbidity management. For patients with NAFLD at risk of disease progression, there is a lack of large, randomized, placebo-controlled trials of adequate treatment duration, with baseline stratification according to histologic severity.

A placebo‐controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection

Adefovir dipivoxil (bis‐POM PMEA) is an adenine nucleotide analogue with activity against retroviruses and herpesviruses, and in vitro activity against hepatitis B virus (HBV). This study was conducted to evaluate its safety and antiviral activity in patients with chronic HBV infection. Twenty patients (13 co‐infected with human immunodeficiency virus, HIV) were randomized in a phase I/II, double‐blind, placebo‐controlled study. Patients who had been hepatitis B surface antigen (HBsAg)/hepatitis B e antigen (HBeAg) positive for ≥ 6 months, with elevated hepatic transaminases and serum HBV DNA ≥ 50 pg ml–1, were randomized to adefovir dipivoxil 125 mg (n = 15) or placebo (n = 5) as a single, daily, oral dose for 28 days. Antiviral activity was assessed by changes in serum HBV DNA (using the Digene Hybrid Capture assay) and HBeAg/hepatitis B e antibody (HBeAb) status. HBV DNA levels fell rapidly by > 1 log10 in all active drug recipients (median fall 1.8 log10 pg ml–1) but increased by 0.01 log10 pg ml–1 in controls (P = 0.002). Reductions were sustained during treatment. HBV DNA returned to baseline over 1–6 weeks following discontinuation of active drug. HBeAg became transiently undetectable in one patient on treatment and, in another, sustained seroconversion to HBeAb occurred 12 weeks after treatment ended. Liver transaminase elevations > 300 U l–1 were observed in three patients during therapy (leading to protocol‐specified treatment discontinuation or dose reduction) and in four patients during follow‐up. On‐treatment transaminase elevations were associated with HIV status, occurring in three of six HIV‐uninfected patients compared with none of nine who were HIV infected. In addition, a slower return to baseline of serum HBV DNA levels was observed in the non‐HIV‐infected patients. Treatment for chronic hepatitis B as a once‐daily oral dose was well tolerated and associated with significant and sustained reductions in serum HBV DNA levels during treatment. Transaminase elevations, which may be related to the therapeutic effect, were observed during and after treatment. Further studies are warranted to investigate the safety, and optimum dose and duration, of adefovir dipivoxil treatment for chronic hepatitis B.

Progression of liver fibrosis in patients with chronic hepatitis C after orthotopic liver transplantation.

Background. Hepatitis C virus (HCV)-related cirrhosis is the leading indication for orthotopic liver transplantation (OLTx). HCV recurrence is universal after OLTx, with a highly variable course. This study aimed to find factors that affect progression of fibrosis in recurrent HCV. Methods. Fifty-eight HCV patients underwent OLTx at our center who were selected on the basis of available preOLTx serum or explanted liver sample and liver biopsy obtained at least 6 months postOLTx. All liver biopsies were performed when clinically indicated and were scored using the modified Hepatitis Activity Index (HAI). Primary immunosuppression consisted of tacrolimus and prednisone. Results. The group included 41 males (mean age 49.6 years). HCV genotype distribution was 1a, 31 (53%); 1b, 16 (28%), and others 11 (19%). The mean follow-up was 53.1 months. Patients with genotype 1a (n=31; mean 46.3 months) had significantly lower fibrosis-free survival analyzed by the presence of fibrosis stages 5 and 6 when compared with other genotypes (n=27; mean 60.1 months; P =0.0088, log rank test). Mean HAI scores were significantly higher in HCV genotype 1a, although there were no differences in survival between genotypes. Similarly, patients with cytomegalovirus (CMV) infection postOLTx (n=4) had a higher fibrosis progression rate compared with those without CMV (n=54) (mean fibrosis-free survival 29.0 vs. 53.0 months P =0.0004, log-rank test). Human leukocyte antigen matching and rate of acute rejection did not influence progression of fibrosis. Conclusion. Patients with HCV genotype 1a and those developing CMV postOLTx have a higher rate of hepatic fibrosis progression after OLTx for HCV-related chronic liver disease.

Caroli's disease and orthotopic liver transplantation

Carolis disease is a rare congenital hepatic disease, characterized by segmental dilatation of the biliary tree. Patients who have recurrent bouts of biliary infection, particularly those with complications related to portal hypertension, may require orthotopic liver transplantation (OLT). Few case reports have described the outcome of OLT in patients with Carolis disease and to date there is no large series reported in the literature. We retrospectively analyzed the outcome of OLT in patients with Carolis disease who underwent OLT between 1982 and 2002 at Starzl Transplantation Institute, University of Pittsburgh. Patients were identified and data was collected by computerized search of the electronic database system. All patients had confirmation of diagnosis by histopathology of explanted liver. A total of 33 patients with Carolis disease were listed for liver transplantation, 3 of whom were excluded, as they were not transplanted. A total of 90% had signs of hepatic decompensation at the time of OLT. Median posttransplantation follow‐up was 7.7 yr. Short‐term graft and patient survival at 1 month was 83% and 86%, whereas overall long‐term graft survival rates at 1, 5, and 10 yr were 73%, 62%, and 53%, respectively, and patient survival rates were 76%, 65%, and 56%, respectively. Long‐term outcome in patients who survived the first year after transplantation was significantly better. Their survival rate at 5 and 10 yr was 90% and 78%. On univariable analysis, recipient age, donor male gender, coexistent congenital hepatic fibrosis, and re‐OLT were associated with poor patient survival. Eight patients were retransplanted, 3 of whom had primary nonfunction. A total of 13 patients died; the most common cause of death being sepsis and cardiovascular complications. Patients who died of sepsis had cholangitis pre‐OLT. In conclusion, OLT is a form of curative and life‐saving therapy in patients with Carolis disease, especially in those with decompensated liver disease. Overall survival is better with liver transplantation and is comparable with the survival of recipients who undergo OLT for other etiologies of chronic liver disease. Survival was poor in patients with congenital hepatic fibrosis (Carolis syndrome) and in those who had cholangitis at the time OLT. Liver Transpl 12:416–421, 2006.

Health-related quality of life: Hepatocellular carcinoma, chronic liver disease, and the general population

Health related quality of life (HRQL) has become an important endpoint in testing the efficacy of treatments for chronic liver disease (CLD) and the consequences of CLD which include hepatocellular carcinoma (HCC) and liver failure. However, a paucity of research on HRQL has been conducted with these patient populations. The aims of the present study were to compare persons diagnosed with HCC to persons diagnosed with CLD as well as with the general population (GP) on a disease-specific instrument measuring HRQL. If significant and clinically meaningful differences in HRQL exist, HRQL may be used as a corroborative indicator of disease progression in patients with CLD. Two hundred and seventy-two people participated in the present study. Of these participants, 83 were diagnosed with HCC, 51 with CLD, and 138 were from the GP. None of the patients in the HCC or CLD samples were actively receiving chemotherapeutic treatments for the CLD or HCC. A sociodemographic questionnaire and the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) was administered to participants. The results of the study suggested that people diagnosed with HCC, prior to treatment, had a poorer overall HRQL when compared to those persons with CLD and the general population, as expected. The differences in HRQL were statistically significant as well as clinically meaningful. People diagnosed with CLD and HCC respectively, reported better social and family well-being than the general population. Furthermore, people with CLD reported equivalent emotional well-being as the general population sample. HRQL subscale scores, with the exception of social and family well-being, discriminated group membership.

Underlying steatohepatitis, but not simple hepatic steatosis, increases morbidity after liver resection: A case‐control study

Despite the high prevalence of fatty liver disease, the safety of liver resection in settings of steatohepatitis (SH) or hepatic steatosis is poorly understood. The aim of this study was to determine whether underlying SH or simple hepatic steatosis increases morbidity after liver resection. We compared patients undergoing liver resection with underlying SH or greater than 33% simple hepatic steatosis to controls selected for similar demographics, diagnoses, comorbidities, preoperative chemotherapy treatments, and extent of partial hepatectomy. Primary endpoints included postoperative overall and hepatic‐related morbidity. One hundred and two patients with SH and 72 with greater than 33% simple hepatic steatosis who underwent liver resection from 2000 to 2011 were compared to corresponding controls. There were no differences in extent or approach of liver resection, malignant indications, preoperative chemotherapy treatment, elements of metabolic syndrome, alcohol use history, American Society of Anesthesiologists score, age, or gender between patients with SH or simple steatosis and corresponding controls. Ninety‐day postoperative overall morbidity (56.9% versus 37.3%; P = 0.008), any hepatic‐related morbidity (28.4% versus 15.7%; P = 0.043), surgical hepatic complications (19.6% versus 8.8%; P = 0.046), and hepatic decompensation (16.7% versus 6.9%; P = 0.049) were greater among SH patients, compared to corresponding controls. In contrast, there were no differences in postoperative overall morbidity (34.7% versus 44.4%; P = 0.310), any hepatic‐related morbidity (19.4% versus 19.4%; P = 1.000), surgical hepatic complications (13.9% versus 9.7%; P = 0.606), or hepatic decompensation (8.3% versus 9.7%; P = 0.778) between simple hepatic steatosis patients and corresponding controls. Using multivariable logistic regression, SH was independently associated with postoperative overall (odds ratio [OR], 2.316; 95% confidence interval [95% CI]: 1.267‐4.241; P = 0.007) and any hepatic‐related (OR, 2.722; 95% CI: 1.201‐6.168; P = 0.016) morbidity. Conclusion: Underlying SH, but not simple hepatic steatosis, increases overall and hepatic‐related morbidity after liver resection. (HEPATOLOGY 2012)

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohns disease (CD) (rG = 0.04) (P = 2.55 × 10−15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10−15). Our study represents a substantial advance in understanding of the genetics of PSC.

Portal Hypertension and Variceal Hemorrhage

Portal hypertension is a progressively debilitating complication of cirrhosis and a principal cause of mortality in patients who have hepatic decompensation. This article describes the classification system and pathophysiology of portal hypertension. It also discusses a practical approach to prevention of first variceal hemorrhage, general management of the acute bleeding episode, and secondary prophylaxis to prevent rebleeding. Pharmacologic, endoscopic, radiologic, and surgical modalities are all described in detail.

Jejunal gastrointestinal stromal tumor: a cause of obscure gastrointestinal bleeding.

In cases of obscure gastrointestinal bleeding, when a source for blood loss is not apparent from examination of the colon and upper gastrointestinal tract, the small bowel usually becomes the focus of investigation. A tumor with interesting pathologic features was found in a patient who presented with recurrent episodes of massive obscure gastrointestinal hemorrhage. This case highlights the importance of considering small intestinal tumors as the likely cause of obscure gastrointestinal hemorrhage in young patients and how a noninvasive test, eg, abdominal computed tomography scan, might obviate the need for more invasive testing.

Severe cholestatic hepatitis in a patient taking acitretin

1. Okamura H, Tsutsi H, Komatsu T, et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 1995;378:88–91. 2. Tanaka F, Hashimoto W, Okamura H, et al. Rapid generation of potent and tumor-specific cytotoxic T lymphocytes by interleukin 18 using dendritic cells and natural killer cells. Cancer Res 2000;60:4838–44. 3. Hashimoto W, Osaki T, Okamura H, et al. Differential antitumor effects of administration of recombinant IL-18 or recombinant IL-12 are mediated primarily by Fas-Fas ligandand perforin-induced tumor apoptosis, respectively. J Immunol 1999;163:583–9.