Briefly noted: M Izzy, J Oh, KD Watt. Hepatology 2018; 68: 2008-2015. This concise review discusses the outcome of cirrhotic cardiomyopathy after liver transplantation.
Key point: “Although it is often believed that cirrhotic cardiomyopathy resolves post-LT, the data, albeit limited, do not support this postulation…diastolic function may not improve post-transplant and may actually worsen. Improvement in systolic function was suggested by only two of six studies.”
Related blog post: Cholecardia
This figure from Hepatology November cover depicts a cirrhotic liver restricting the heart filling during diastole. (From Wiley Online Library -free access)
Despite widespread recommendations to screen patients with cirrhosis for hepatocellular carcinoma (HCC), a recent study (AM Moon et al. Gastroenterol 2018; 16: 1777-85) found “No Association Between Screening for Hepatocellular Carcinoma and Reduced Cancer-Related Mortality in Patients with Cirrhosis.” The title of the study did not make sense to me based on previous publications that have noted increased risk of HCC in patients with cirrhosis and the presumption that screening would allow effective interventions to prevent death due to HCC. So I looked at the study a little closer:
Background/Methods: The authors utilized a matched case-control study within the U.S. Veterans Affairs health care system to determine whether ultrasonography (US) or alpha-fetoprotein (AFP) screening was associated with decreased cancer-related mortality.
They identified 238 patients with cirrhosis who died of HCC between 2013-2015 –all of whom had a diagnosis of cirrhosis at least 4 years before the diagnosis of HCC. Then, they matched them with a control patient with cirrhosis who did not have HCC and had been identified at least 4 years prior to matched case’s HCC.
- There was no significant difference between the cases and the controls in the proportions who underwent screening:
- For U/S screening: 52.9% cases and 54.2% for controls.
- For AFP (serum) screening, 74.8% vs 73.5% respectively.
- For either U/S or AFP screening, 81.1% vs 79.4%.
- For both U/S and AFP screening, 46.6% vs 48.3% respectively.
- Table 4 provides odds ratios and adjusted odds ratios for the cases compared to controls. The Adjusted Odds ratios for U/S 0-4 years before index case was 0.95, for AFP 1.08, and for either U/S or AFP 1.11.
The authors found that HCC screening with U/S and/or AFP was not associated with decreased risk of HCC-related mortality.
In their study, the authors note that most studies on HCC screening have been observational which have numerous limitations including lead-time biases (which can overestimate the benefits of screening) and patient selection. Two randomized controlled trials reached conflicting conclusions; these trials were conducted in China where HCC is mainly associated with hepatitis B infection.
The authors point out that liver societies like AASLD and EASL have recommended U/S every 6 months with or without AFP measurements for HCC surveillance in patients with cirrhosis. However, non-liver societies have NOT “endorsed HCC screening because of the lack of high-quality data.” Neither the US Preventive Services Task Force nor the American Cancer Society make recommendations for HCC screening. And, “the National Cancer Institute found no evidence that screening decreases mortality from HCC but did find evidence that screening could result in harm.”
Strengths of this study:
- All VA patients have access to medical care; this limits bias due to access to HCC screening
- The matched-case control design with random controls across a system that delivers care to 8 million veterans across the country indicates that the findings are likely “typical of community-based settings” and likely to yield “estimates of the impact of screening …[that] approximates the results that would be expected from a randomized controlled trial”
Why Have Previous Studies Indicated that HCC Screening is Worthwhile?
- According to the authors, even though HCC detected by screening is on average detected at an earlier stage than those detected due to symptoms, “this does not prove that screening leads to earlier detection. Another explanation is that screening is more likely to identify slow-growing tumors, which have a lower stage, and more likely to miss the fast-growing tumors, which are identified at a higher stage by symptoms.”
- “It is possible that the HCCs most likely to lead to death are the HCCs least likely to be identified by current screening modalities at an early stage.”
- In addition, “whether early treatment for HCC in patients with cirrhosis leads to a decrease in case fatality is questionable.” Patients who receive surgical resection or locoregional treatments remain at risk for recurrent HCC, new HCC and progressive liver dysfunction. While liver transplantation can cure HCC and cirrhosis, only a “small minority of patients with HCC undergo liver transplantation.” In 2012, only 1,733 patients received liver transplantation for HCC out of a reported 24,696 incident cases.
My take: This study offers a lot of insight regarding HCC screening and questions its usefulness, though I doubt this study will change how most hepatologists practice.
Related blog posts:
A survey (O Waisbourd-Zinman, et al. JPGN 2018; 66: 447-49) of 44 pediatric hepatologists (with 935 years of clinical practice) examined the issue of splenic rupture and spleen guards. ~90% of those surveyed reported following at least 30 patients with portal hypertension and splenomegaly.
- In total, the hepatologists could recall 13 cases of splenic rupture among patients with portal hypertension/splenomegaly due to cirrhosis –almost all of these occurred after a fall or in a motor vehicle accident. Only one of these falls happened during a sports-related event (soccer).
- 11 cases were serious. 9 of these cases resulted in shock with subsequent splenectomy, embolization, and/or death. Death reported in 2 cases.
- In this survey, 61% of hepatologists recommended “absolute restriction from activity with high risk of blunt abdominal trauma;” whereas 23% indicated that activities with risk of blunt trauma were acceptable if wearing a spleen guard.
- To prevent splenic rupture in patients with portal hypertension/splenomegaly, among the participating hepatologists, the majority identified the following ‘high risk’ sports: football (95%), hockey (82%), and wrestling (66%). A smaller percentage advocated a spleen guard for skiing (42%), soccer (41%), basketball (30%) and other sports.
While I did not participate in this survey, the one patient with chronic liver disease that I followed who had a splenic rupture had fallen down a flight of steps; fortunately, he recovered with supportive care.
My take: This survey shows that there is wide variability in the use of spleen guards. In almost all cases of splenic rupture, this was precipitated by severe trauma. Though, patients with portal hypertension may avoid high contact sports and thus the risks are for these sports is unclear.
Related blog post:
Foggy Morning in Sandy Springs
A concise and useful review of nonalcoholic steatohepatitis (NASH): AM Diehl, C Day. NEJM 2017; 377: 2063-72
A couple points:
- About 25% of adults have fatty livers in the absence of excessive alcohol consumption
- NASH is strongly associated with obesity/overweight which occur in >80% of patients
- NASH comorbidities in adults: 72% with dyslipidemia, 44% with type 2 diabetes mellitus
- In a typical patient with NASH, liver fibrosis progresses “at a rate of approximately one stage per decade, suggesting that F2 fibrosis will progress to cirrhosis within 20 years.” However, there is considerable variability.
- It is expected that NASH will be the leading reason for liver transplantation by 2020.
- Cirrhosis related to NASH increases the risk of hepatocellular carcinoma with this occuring in 1-2% per year of patients with cirrhosis.
- NASH is estimated to cost >$100 billion currently in annual direct medical costs
- Staging of NASH and differentiation from isoloated steatosis identifies those at high risk for sequelae.
- In Table 2, the authors list more than 10 pharmacologic agents in phase 2/3 studies
Current lifestyle treatment recommendations (for adults):
- Lose 7% of body weight if overweight or obese
- Limit consumption of fructose-enriched beverages
- Limit consumption of alcohol (no more than 1 drink/day for women and 2 drinks/day for men)
- Drink two or more cups of caffeinated coffee daily
Related blog entries:
Panels A & B show typical histologic findings: ballooned hepatocytes (arrows), inflammatory infiltrates (arrowheads), and fibrosis Panel C shows the relative distribution of NASH, cirrhosis, and hepatocellular carcinoma in U.S. Adults.
There have been a number of studies suggesting a beneficial effect of statins for individuals chronic liver disease due to HBV infection, HCV infection, and nonalcoholic steatohepatitis. The potential reasons include lower portal hypertension due to increased nitric oxide availability, anti-inflammatory effects through reduction in some cytokines, and antifibrotic effects. In addition, statins may inhibit tumor initiation/hepatocellular carcinoma (HCC).
The background on these prior studies is detailed in a new population-based study (F-M Chang et al Hepatology 2017; 66: 896-907, editorial 697-9) of statins in patients with cirrhosis. In this nested case-control study from Taiwan, the authors examined patients (n=1350) with cirrhosis from 2000 to 2013. The index cases of cirrhosis were identified among a representative, well-validated general population database of 1,000,000 people.
- “Statin use decreased the risk of decompensation, mortality, and HCC in a dose-dependent manner.”
- Risk of decompensation among chronic HBV statin users, HR 0.39
- Risk of decompensation among chronic HCV statin users, HR 0.51
- Risk of decompensation among alcohol-related cirrhosis patients taking statins, HR 0.69
My take: In adults with cirrhosis, particularly HBV-related and HCV-related, taking a statin was associated with a 50-60% lower likelihood of decompensation. A prospective study could confirm these findings.
Prague -Charles Bridge
Briefly noted: The authors of a recent study (E Ceunen et al. Clin Gastroenterol Hepatol 2016; 14: 1552-58) set out to study whether it is likely that healthy adults could learn to fear “innocuous visceral sensations.” Fifty-two healthy subjects received 2 types of esophageal balloon distentions –one that was perceptible and non-painful and one that was painful. Not surprisingly, when the researchers paired these two interventions in the experimental group, the experimental group learned to fear the innocuous stimulation as well as the painful distention. This study provides theoretical support for one mechanism that could trigger ongoing functional gastrointestinal symptoms and a potential rationale for therapies, like cognitive behavioral therapy, which attempt to extinguish these symptoms.
In a retrospective study (AM Moon et al. Clin Gastroenterol 2016; 14: 1629-37) with 6451 patients with cirrhosis (mean age 60.6 yrs), the authors note that use of antibiotics during upper gastrointestinal bleeding (which is currently recommended) is associated with reduced mortality by ~30% at 30 days. Despite its benefit, this intervention is often overlooked. In the current study, only 48.6% of admissions received timely antibiotics; however, during the course of the study, the rate of antibiotic use improved from 30.6% in 2005 to 58.1% in 2013.
A recent retrospective study (N Goossens et al. Clin Gastroenterol 2016; 14: 1619-28) with 492 subjects showed that histologic NASH (in 12% of cohort) was associated with increased risk of death in patients who underwent bariatric surgery compared to patients without NASH. Overall, bariatric surgery reduced the risk of death during the study period with HR of 0.54; the median follow-up was 10.2 years, with surgery taking place 1997-2004. However, in patients with NASH the HR 0.90 which indicated that there was not a significant reduction in the risk of death.
Bar Harbor, ME (low tide)