Withdrawal of Chronic Hepatitis B Therapy

G Hirode et al. Gastroenterol 2022; 162: 757-771. Off-Therapy Response After Nucleos(t)ide Analogue Withdrawal in Patients With Chronic Hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study)

Methods: This cohort study included patients (n=1552) with virally-suppressed chronic hepatitis B (CHB) who were hepatitis B e antigen (HBeAg)–negative (and without advanced liver disease) and stopped nucleos(t)ide analogue (NA) therapy

Key findings:

  • Cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up
  • HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; P < .001) and among patients with HBsAg levels <100 IU/mL at end of therapy (vs ≥100 IU/mL: subdistribution hazard ratio, 22.5; P < .001)

My take: This study identifies subsets with HBeAg-negative CHB who may benefit from NA therapy cessation.

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Why Do Some People Recover from Acute Liver Failure and Some People Don’t?

Briefly noted: T Lin et al. Hepatology 2022; 322-337. Open Access: Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure

Design: After preliminary work in 19 patients with acute liver failure (ALF) and in a zebrafish model, a prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin (FST) levels in prevalence and mortality of acute-on-chronic liver failure.

Key findings: Recovered patients with ALF robustly express HNF4α in either LPCs (liver progenitor cells) or remaining hepatocytes. Serum FST levels could predict the incidence and mortality of acute-on-chronic liver failure.

Implication of study: “Our results indicate that serum FST levels might be a surrogate marker reflecting the extent of hepatocyte death and hepatic insulin resistance, which point to the danger of coagulopathy and clinical deterioration. The hypothesis requires further confirmation in the future.”


Hormone-controlled activin-HNF4α-coagulation factor axis in LPCs

How Often Does Liver Disease Develop in Healthy Young Males…Over 65 Year Study Period

J Uhanova et al. Clin Gastroenterol Hepatol 2021; 19: 2417-2424. Chronic Liver Disease and Metabolic Comorbidities in Healthy Young Males Followed for 65 Years: The Manitoba Follow-up Study

Methods: 3,983 air force men were enrolled in the Manitoba Follow-up Study in 1948. The comprehensive database on results of routine physicals and health encounters was examined for evidence of chronic liver disease (CLD) and metabolic syndrome (MetS). 

Key findings:

  • 5.2% of men developed CLD and 6.4% MetS
  • Among the 206 with CLD, 162 (79%) were diagnosed with CLD as a non-terminal event; however, CLD was clinically significant with 50.5% (n=104) with cirrhosis (of whom 56 had hepatic decompensation)
  • The most common etiologies for CLD were alcohol-related liver disease (32.5%, n=67) and fatty liver disease (20%, n=41); chronic viral hepatitis (B & C) accounted for 4.4% (n=9). In 20%, the etiology was not specified
  • The relative risk of mortality in men with vs. without CLD was 3.33 (95% CI – 2.83 to 3.91, p < .0001)
  • An increasing gradient of risk for CLD was apparent with increasing numbers of MetS components; the HR of 3.67, 5.97 and 14.3 for IR/DM (insulin resistance /diabetes mellitus), IR/DM + one component, and IR/DM + two or more components respectively

Discussion –The authors note that the lifetime risk of CLD was much higher in NHANES studies (11.8% to 14.8% prevalence); this is attributed to active surveillance for liver disease in the NHANES study (and different study population). It is also likely that there is a substantially increased risk over the last 65 years due to factors like increasing rates of obesity as well as possibly higher rates of alcohol use and infections.

My take: Among healthy 18 year old males, a substantial number develop chronic liver disease, much of which could be prevented by limiting alcohol intake and maintaining a healthy diet/exercise.

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Intracostal Waterway near Siesta Key, FL

Changes in Latitudes and Changes in Autoimmune Liver Disease

GJ Webb et al. Clin Gastroenterol Hepatol 2021; 19: 2587-2596. Open Access: The Epidemiology of UK Autoimmune Liver Disease Varies With Geographic Latitude

Methods: A retrospective cohort study using anonymized UK primary care records (2002-2016). All adults without a baseline diagnosis of AILD (autoimmune liver disease) were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database.

AIH, autoimmune hepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis

Key findings:

  • 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34–2.60); PSC, 0.74 (95% CI, 0.67–0.82); and AIH, 1.94 (95% CI, 1.83–2.06) per 100,000 per year.
  • A more northerly latitude was associated strongly with incidence of PBC: 2.16 to 4.86 from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 to 3.28 (P = .003), but not incidence of PSC: 0.82 to 1.02 (P = .473)
  • After adjustments, PBC was more frequent in smokers than those who had never smoked at 3.40 (3.03–3.77) per 100,000/y and 1.96 (1.80–2.12) cases per 100,000/y; there was a lower incidence of PSC in smokers 0.47 (0.33–0.61) per 100,000/y compared with those who had never smoked 0.95 (0.83–1.07) per 100,000/y. For AIH, there was no difference between current smokers and those who had never smoked

The authors speculate in the discussion about potential reasons why latitude could correlate with disease incidence. Some potential explanations include sunlight/vitamin D metabolism (though this is at odds with the fact that those with increased skin pigmentation are NOT at increased risk), environmental exposures (related to geology, diet, air quality) or unrecognized genetic tendency based on geography.

My take: In the UK, there is an association between a more northernly latitude and both PBC and AIH.

Related blog post: Aspen Webinar 2021 Part 5 -Autoimmune Liver Disease & PSC

Figure 2

Mortality Risk With Autoimmune Hepatitis

R Sharma et al. Clin Gastroenterol Hepatol 2021; 19: 2636-2647. Open Access PDF: Increased Mortality Risk in Autoimmune Hepatitis: A Nationwide Population-Based Cohort Study With Histopathology

In this nationwide population-based cohort study in Sweden from 1969-2017 of 6,016
adults with histologically-confirmed AIH (all 18 years or older) and 28,146 matched general population, key findings:

  • 3,185 individuals with AIH died (41.4/1000 person-years) compared with 10,477 reference individuals (21.9/1000 person-years)
  • The 10-year cumulative incidence of death was 32.3% (95%CI [ 31.1-33.6) for AIH individuals and 14.1% (95%CI [ 13.7-14.5) for reference individuals
  • AIH individuals with cirrhosis on biopsy had a high risk of death (HR [ 4.55; 95%CI [ 3.95-5.25), while mortality risks for patients with noncirrhotic fibrosis (HR, 2.68) and inflammation without fibrosis (HR, 2.18) were similar to overall risk
  • In this cohort, 13.7% had cirrhosis at diagnosis (lower than other studies)

My take: In this study over nearly 50 years, AIH was associated with “a 2-fold increased risk of death. Risks were particularly high in individuals with cirrhosis, portal hypertension (HR, 7.55), and overlap with cholestatic liver disease.”

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Hepatitis C Relapse After Treatment –Spontaneously Cleared in Some

H Kuriry et al. Clin Gastroenterol Hepatol 2021; 19: 2398-2406. Spontaneous Clearance After Relapse Following Direct-Acting Antiviral Treatment for Chronic HCV Infection

This retrospective case-control study identified 93 patients out of 1032 with chronic HCV infection who had a relapse of detectable infection following treatment. Key findings:

  • 12 patients (13%) spontaneously cleared HCV within 6 months after the documented relapse without additional therapy
  • The spontaneous clearers had low levels of HCV RNA (<4 log IU/mL in 11 of 12) and normal levels of alanine aminotransferase at the time of relapse. Low level RNA was identified in only 1 persistent relapser
  • There was no significant difference between the spontaneous clearance group and the SVR12 group in magnitude and breadth of HCV-specific T cell responses
  • The authors note that one limitation of the study was a false positive PCR assay –though this does not negate their message that retesting is important before retreatment
  • The relatively high relapse rate (9%) in this cohort is likely related to the use of first-generation DAA therapy
  • The timing of retesting in the 12 with spontaneous clearance was variable. 7 who had repeat testing at 3 months were all negative.

My take: In those with a low level virological relapse after DAA therapy for HCV, it is a good idea to repeat testing before consideration of further treatment.

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Huntingdon Lake, Sandy Springs (from Suzan)

Ongoing Hepatitis B Susceptibility in U.S. Adults

H Roberts et al. Hepatology 2021; 74: 2353-2365. Prevalence of HBV Infection, Vaccine-Induced Immunity, and Susceptibility Among At-Risk Populations: US Households, 2013-2018

This article provides some useful trends in Hepatitis B virus (HBV) epidemiology based on NHANES surveys (National Health and Nutrition Examination Survey).  Persons who tested negative for anti-HBc, HBsAg, and anti-HBs were considered susceptible to HBV infection.

Key Findings:

  • The estimated prevalence of persons living with chronic hepatitis B in the USA has remained unchanged at 0.3% since 1999. During 2013-2018, this accounted for 880,000 US residents who were living with chronic HBV infection. It is noted that only a minority of the 11.7 million residents with a history of HBV develop chronic HBV
  • The non-US-born population accounted for 69% (610,000) of persons living with chronic HBV and 70% of this group were Asian. Non-US born population had a 9-fold risk of chronic HBV compared to US-born persons
  • Among adults aged ≥ 25 years who resided in US households, an estimated 155.8 million persons (or 73.4%) were susceptible to HBV infection. Susceptibility was lower in the 25-49 age group (64.8%) compared to the 50 years and older group (81.6%)
  • Despite vaccine recommendations, at risk groups including those using illicit drugs, hx/o MSM, and HCV exposure continue to have high susceptibility; fewer than 25% of adults “deemed to be at high risk for contracting HBV infection had vaccine-induced immunity
  • Overall, vaccine-induced immunity increased to 21.4% (2013-2018) compared to previously 17.9% (2007-2012) in those 25 years and older
  • Limitations: lack of detectable anti-HBs is likely to overestimate susceptibility in those who have previously been vaccinated, participation in NHANES by non-US born persons may have been unequal, and determining timing of HBV acquisition by non-US born persons was not feasible in this study

My take: Lots of adults have chronic HBV and lots more are susceptible. How to identify and encourage adults to avoid vaccine-preventable illnesses is NOT getting easier.

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From NPR 12/5/21

NY Times: “Who Deserves a Lifesaving Organ?”

NY Times: “Who Deserves a Lifesaving Organ?”

Yesterday’s post discussed policy efforts to help with equitable access for transplantation. This essay explores some of the same issues.

A few excerpts:

  • What makes someone a “good” transplant candidate? Maybe it is inevitable that doctors’ biases creep in when we must make fraught decisions about a scarce resource….
  • A transplant program is also beholden to its metrics. If the one-year survival of transplant recipients is lower than expected or if transplant failure is higher than expected, a program could be put on probation or lose its certification entirely…
  • Social-support requirements vary based on the intensity of the surgery and the length of the required rehabilitation. But in general, a patient is expected to have one to three people who can commit to helping in recovery — driving to appointments, managing medications or responding to overnight emergencies…
  • So much of transplant decision-making is about narrative, which is one reason misconceptions can take hold when patients do not speak English as their primary language. Hispanic patients are about half as likely as their white peers to receive kidney donations from family or friends— a gap that Dr. Juan Carlos Caicedo, an adult and pediatric transplant surgeon who directs the Hispanic Transplant Program at Northwestern Medicine, is working to close. “People will argue that these are not good patients because they don’t follow recommendations, but they are dead wrong,” he told me. “They are great patients, as long as they understand you.”..
  • Change is happening. At my hospital, our lung transplant team is working to identify recipients from underserved communities who can become “ambassadors” to educate others and build trust…
  • Perhaps most important, transplant teams are openly discussing and challenging their assumptions about who makes a “good” transplant candidate. And in doing so, more lives may be saved.
Thanks to Jennifer for this picture

Equitable Access to Liver Transplant

R Rosenblatt et al. Hepatology 2021; 74: 2808-2812. Open Access. Equitable Access to Liver Transplant: Bridging the Gaps in the Social Determinants of Health

The problem:

“Evaluation for organ transplantation, a life-saving procedure, involves a multistep, highly selective process. Initially, referrals to appropriate subspecialists and a transplant center are required. During evaluation, candidates undergo formal assessment of adequate social support, psychological health, health insurance, adherence, and understanding of treatments. Each step in the transplant evaluation process is an opportunity for inequity to insert itself, resulting in disparate access to listing for transplantation. This manifests through mechanisms related to poor health literacy, lack of insurance or high copay, poor social support, and geographical location. Culture incapacity by health providers and implicit bias at the provider level and health care system level can create additional barriers. Examples of health inequities include lower referral rate for LT and inferior outcomes among Black and Latinx compared to White patients,(3) while, in addition to race/ethnicity, sex and health literacy(4) also strongly correlate with the likelihood of listing. SES [socioeconomic status] affects both waitlist mortality and post-LT survival as well.”

This article proposes policy measures to counter the deleterious effects of SDOH [social determinants of health]—identify and reduce implicit bias, expand and optimize telemedicine, and improve community outreach. “Structural racism, access to affordable insurance, health literacy, and substance abuse therapy are equally important factors that contribute to health disparities and inequities and warrant further commentary and research, but are outside the focus of this policy piece.”

Related blog post: Getting a Seat at the Liver Counter

Quantifying the Cancer Risk (Mainly HCC) in Adults with NAFLD

TG Simon et al. Hepatology 2021; 74: 2410-2423. Open Access. Cancer Risk in Patients With Biopsy-Confirmed Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study

Key findings from this retrospective study with median of 14 yrs f/u (1966-2016, n=8892):

  • HCC incidence rates increased monotonically across categories of simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis (0.8 per 1,000 PYs, 1.2 per 1,000 PYs, 2.3 per 1,000 PYs, and 6.2 per 1,000 PYs, respectively; Ptrend < 0.01) and were further amplified by diabetes (1.2 per 1,000 PYs, 2.9 per 1,000 PYs, 7.2 per 1,000 PYs, and 15.7 per 1,000 PYs, respectively
  • “Compared with controls, patients with NAFLD had a17-fold higher rate of developing HCC and a 20-year absolute excess risk of 2.1%.”
  • The 20-year absolute excess risk of patients with noncirrhotic NAFLD fibrosis (4.6%) or cirrhosis (11.4%) developing HCC was comparable to that of all EHSO [extrahepatic solid organ] cancers combined (4.7% -11.4%).
  • The risk of extrahepatic solid organ cancers was increased 12% compared to general population

G Chonlakeril et al. Hepatology 2021; 74: 2336-2338 Associated Editorial. NAFLD and HCC: Time to Bridge the Gap

  • In this analysis, the authors note the annual incidence rate of HCC for cirrhosis in NAFLD was 0.62% which is below rate of 1.5% in which “HCC surveillance may be cost-effective;” however, the rate was 1.52% in those with cirrhosis and diabetes.
  • The authors note that the 9-fold higher risk for HCC in those with simple steatosis compared to matched population could be related to ascertainment bias (at least in part) as not all patients with steatosis undergo a liver biopsy; in addition, misclassification of liver biopsies is possible.

My take: Lots of increased risk with fatty liver disease, especially increased HCC/cancers and increased cardiovascular disease.

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