Category Archives: Hepatology

When Can You Safely Stop Nucleos(t)ide Treatment for Hepatitis B? & Reassessment of Ventilator Success for COVID-19

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A recent commentary (KS Liem et al. Gastroenterol 2020; 158: 1185-90) reviews the challenge of stopping nucleos(t)ide (NUC) treatment for chronic hepatitis B viral (HBV) infection.

Key points:

  • NUC therapy “prevents liver failure, decreases the risk of hepatocellular carcinoma, and has excellent safety”
  • Yet, there are “low rates of on-therapy functional cure” which is indicated by loss of HBV surface antigen [HBsAg]
  • Divergent recommendations: Guidelines “recommend NCU therapy in noncirrhoitic patients can be stopped after >3 years of virologic suppression (EASL), after ≥1 year of undetectable HBV DNA and 2 years of treatment (APASL), or only after achieving HBsAg loss (AASLD)
  • “Relapse is highly variable, but is especially dangerous in patients with stage 3 fibrosis or cirrhosis”
  • “Hepatic decompensation is relatively rare but is best prevented by continuing NUC therapy in all cirrhotics or those with advanced fibrosis.”
  • In a randomized controlled trial in Canada, 72 weeks after NUC discontinuation, “only 33% of pretreatment HBeAg-negative patients had a sustained off-treatment response.”
  • “The major guidelines suggest that noncirrhotic pretreatment HBeAg-positive patients can stop NUC therapy after reaching HBeAg seroconversion with undetectable HBV DNA and completing 1-3 years of consolidation therapy…these recommendations are of poor quality.”
  • Three issues need to be studied: retreatment criteria in those who stop NUC therapy, biomarkers to distinguish beneficial from detrimental flares, and better criteria for identifying those who are likely to decompensate.

My take: It is hard to argue with the author’s conclusion that “without the tools for proper patient selection, potential benefits of NUC discontinuation do not outweigh limitations of long-term NUC therapy for most patients in clinical practice.”  This is due to the safety of NUC therapy and the frequency of relapse when NUC is stopped.

Related blog posts:

From NPR: New Evidence Suggests COVID-19 Patients On Ventilators Usually Survive

An excerpt:

A study of some New York hospitals seemed to show a mortality rate of 88%. But Cooke and others say the New York figure was misleading because the analysis included only patients who had either died or been discharged. “So folks who were actually in the midst of fighting their illness were not being included in the statistic of patients who were still alive,” he says….

The mortality rate among 165 COVID-19 patients placed on a ventilator at Emory was just under 30%. And unlike the New York study, only a few patients were still on a ventilator when the data were collected.

Curbside Humor:

Also: What do you get from a pampered cow? Spoiled milk!

 

Alpha-1-Antitrypsin Deficiency

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A recent terrific review on Alpha-1-Antitrypsin (A1AT) Deficiency: P Strnad et al. NEJM 2020; 382: 1443-55

Background:

  • 95% of A1AT deficiency is due to homozygosity for the Z allele; prevalence of 1 in 2000 in those of European descent.
  • A1AT protects the lung tissue against attack by the enzyme neutrophil elastase.
  • The presence of A1AT genetic variants suggests that these mutations may confer a selective advantage, perhaps by amplifying the inflammatory response to invasive respiratory/gastrointestinal infections.

Pathophysiology/Clinical Features:

  • Table 1 lists the key alleles/mutations associated with A1AT deficiency -17 deficiency/null listed including: F, I, Iners, King’s, M-malton, M-procida, Pittsburgh, Queen’s, S, S-iyama, Z, QO-bellingham, QO-granitefalls, QO-hongkong
  • S allele deficiency often results in disease (emphysema, cirrhosis) in the setting of SZ heterozygotes.  The disease is typically less severe than in ZZ disease.  This allele is the most common deficiency variant (1 in 5 in Southern Europe, 1 in 30 in U.S.)
  • Z allele deficiency is the most common severe deficiency variant.  Carrier frequency: 1 in 27 persons in Northern Europe, 1 in 83 in the U.S. It is NOT seen in China, Japan, Korea, Malaysia, or Northern and Western Africa.

PI ZZ Genotype:

  • 73% of infants with PI ZZ genotype had elevated ALT level in the 1st 12 months of life
  • Cholestatic jaundice noted in 10% of infant; 15% of these infants progress to juvenile cirrhosis
  • Only 15% with abnormal ALT values by 12 years of age
  • 35% of adults with ZZ genotype show clinically-significant liver fibrosis. Risk factors for advanced fibrosis: male gender, metabolic syndrome/obesity, and alcohol consumption.

Lung Disease Due to A1AT Deficiency:

  • The clinical features of lung disease due to A1AT deficiency are “mainly indistinguishable from those of nonhereditary emphysema…this is partly why severe A1AT deficiency remains undiagnosed in approximately 90% of case, with an interval of 5 to 7 years from the onset of symptoms to diagnosis.”  When the diagnosis is late, lung disease has become irreversible.
  • Early diagnosis allows lifestyle changes (eg. smoking cessation), reduction in occupational risks, and access to therapies.

MZ Phenotype:

PI MZ genotype is more susceptible to multiple disorders, including a predisposition to COPD (at least among smokers) with odds ratio of 1.4.  Other conditions with increased risk: NAFLD-related cirrhosis (OR 3-7), Alcoholic cirrhosis, and CF-associated liver disease

Treatment:

  • Smoking cessation
  • Plasma-purified A1AT infusions.  “Randomized, controlled trials have focused on decreased loss of lung density as the primary efficacy outcome;” however, augmentation therapy has not been to shown to effect other measures, “such as FEV1, quality of life, or exacerbation of COPD.”

Related blog posts:

Also, this study was previously alluded to by this blog, but now is in print:

Briefly noted: X Lu et al. SARS-CoV-2 Infection in Children (NEJM 2020; 382: 1663-5). In 171 Chinese children with confirmed SARS-CoV-2 infection, 41.5% had fever during illness; 27 (15.8%) had no symptoms of infection or radiographic findings. Three required ICU/ventilator support; all had coexisting conditions.  One 10 month old child with intussusception died.

“Crushing it:” Practice Guidance for Hepatitis C

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Today’s post on Hepatitis C follows a few screenshots from twitter regarding the coronavirus epidemic.

Pediatric report of coronavirus in children: NEJM Full link: SARS-CoV-2 Infection in Children A recent review of 72,314 cases by the Chinese Center for Disease Control and Prevention showed that less than 1% of the cases were in children younger than 10 years of age (n=171)…3 patients required intensive care support and invasive mechanical ventilation; all had coexisting conditions. There was one death in a 10-month-old child with intussusception had multiorgan failure and died 4 weeks after admission.

——-

As noted yesterday, this post will review a recent practice guidance for hepatitis C

Some specific recommendations for children:

Testing:

  • “All children born to HCV-infected women should be tested for HCV infection. Testing is recommended using an antibody-based test at or after 18 months of age.”
  • “Testing with an HCV-RNA assay can be considered in the first year of life, but the optimal timing of such testing is unknown” (but can be done as early as 2 months of life).
  • “The siblings of children with vertically-acquired chronic HCV should be tested for HCV infection, if born from the same mother.”

Counseling for parents:

  • “Parents should be informed that hepatitis C is not transmitted by casual contact and, as such, children with HCV infection do not pose a risk to other children and can participate in school, sports, and athletic activities, and engage in all other regular childhood activities without restrictions.”
  • “Parents should be informed that universal precautions should be followed at school and in the home of children with HCV infection. Educate families and children about the risk and routes of HCV transmission, and the techniques for avoiding blood exposure, such as avoiding the sharing of toothbrushes, razors, and nail clippers, and the use of gloves and dilute bleach to clean up blood.”

Treatment:

  • “Direct-acting antiviral (DAA) treatment with an approved regimen is recommended for all children and adolescents with HCV infection aged ≥3 years as they will benefit from antiviral therapy, regardless of disease severity.”
  • Early treatment in childhood is expected to be cost-effective compared to treatment at later ages based on previous studies

This chart provides recommendations for pediatric patients who have not received prior direct-acting antivirals. More information at HCVguidelines.org

Lifesaving APPs (Advanced Practice Providers)

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A recent study (EB Tapper et al. Hepatology 2020; 71: 225-34, editorial 11-13) shows that advanced practice providers (APPs) provide care that translates into better outcomes for adults with cirrhosis.  APPs include physician assistants and nurse practitioners.

In a retrospective analysis (2001-15) of the Optum Clinformatics database (private insurance) with 389,257 adult patients, the authors show that patients who had an APP involved in their care had better outcomes.

Key findings among patients with APP care (with and without specialist involvement):

  • Reduced risk of death, aHR 0.43
  • Improved metrics: higher HCC screening aOR 1.23, higher variceal screening OR 1.20, increased use of rifaximin after discharge for HE OR 2.09, and reduced risk of hospital 30-day readmission OR 0.68.
  • Overall, AAP care alone was inferior to specialist care alone for all metrics except 30-day readmissions; however, shared care (APP and specialist care) was more successful than specialist care alone (eg. 30-day readmissions OR 0.91 with shared care)
  • APP involvement was associated with an almost 2-fold increase in costs per person per year (~$9600 compared to $4500) and increased procedures
  • Due to the retrospective nature, it is unclear how many of the APPs had specialty training; as such, it is not clear whether primary care APP involvement is equivalent to specialty care APP involvement

My take: Based on my experience, this study likely could be replicated in most medical fields.  APPS improve patient outcomes.

Island Ford National Recreational Area, Sandy Springs

Is Tenofovir the Best Medication for Hepatitis B Infection?

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Two recent studies have suggested that tenofovir may be more effective for hepatitis B virus (HBV) infections.

  • T C-F Yip et al. Gastroenterol 2020; 158: 215-25.
  • J Choi et al. JAMA Oncol 2019; 5: 30-6. (Reviewed in a commentary by P Lampertico, M Colombo. Gastroenterol 2019; 157: 1682-88)

In the first retrospective study from Hong Kong, the authors analyzed 29,350 consecutive treated-patients  (mean age 52.9 years).  1309 were treated with tenofovir disoproxil fumarate (TDV) and 28,041 were treated with entecavir. Key findings:

  • TDF-treated patients were younger (mean age 43.2 years vs. 53.4 years) and had less cirrhosis at baseline (2.9% vs. 13.6%).
  • After a median follow-up of 3.6 years, 8 TDF-treated patients (0.6%) and 1386 (4.9%) of entecavir-treated patients developed hepatocellular carcinoma (HCC).  The authors note that TDF maintained a lower rate of HCC after propensity score weighting (hazard ratio of 0.36)

The second study was a nationwide population cohort database with >24,000 patients –all with ALT >80. Key finding:

  • HCC was significantly lower in TDF group than in the entecavir group, the percent person-years being 0.64 compared to 1.06; though, there was not a lower mortality rate or a lower liver transplantation rate.

The commentary associated with the latter study makes the following points:

  • Both TDF and entecavir could prevent “the incidence and mortality of HCC …in >85% of patients who received [them] for years.”
  • Studies comparing TDF and entecavir have come up with conflicting results.  “Three studies in Korea, the U.S, and Europe reported no differences between NAs even after patient matching by a propensity score.”
  • “Cumulatively, all these studies deliver the reassuring message of a robust risk reduction of liver cancer taking place in patients with chronic hepatitis B who experience prolonged virus suppression after NA therapy, but currently they fail to provide convincing evidence that one NA is superior to the other one in determining such clinical benefit.”

My take: Tenofovir may be better but the answer is not definitive; due to lack of randomization, there may still be confounding variables in which sicker patients are receiving entecavir and this could be contributing to the difference in outcomes.  Also, in patients with bone disease and renal impairment, tenofovir alafenamide (TAF) or entecavir is recommended.

Related blog posts:

From P’tit Train Du Nord Linear Park

Bad Fatty Liver Disease Can Get Worse Quickly

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A recent study (AJ Sanyal et al. Hepatology 2019; 70: 1913-27) used prospectively collected data from two large randomized, placebo-controlled phase 2b studies of simtuzumab in patients with either bridging fibrosis (n=217) or compensated cirrhosis (n=258) due to nonalcoholic fatty liver disease (NAFLD). The age range of participants were 48-61 years with median ages of 55 years and 57 years for the two cohorts.  All patients had liver biopsies at screening and at weeks 48 and 96.

Key findings:

  • Progression to cirrhosis occurred in 22% (48/217) of patients with bridging fibrosis (F3) over a median of 29 months
  • Liver-related adverse clinical events (eg. ascites, variceal bleeding, encephalopathy, MELD score ≥15, liver transplantation or death) occurred in 19% (50/258) with compensated cirrhosis over a median of 29 months. Only 1 patient in this cohort died.
  • Higher  baseline hepatic fibrosis or serum markers of fibrosis were associated with disease progression in patients with F3 disease

My take: Among those with advanced liver disease, this study indicates that disease progression/deterioration is rather rapid in about 20%.

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 P’tit Train du Nord Linear Park (near Montreal) -124 Miles

NY Times: Easy Slopes, Please: Biking the Mountains of Quebec 

Outcomes of Liver Transplantation in Small Infants

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A recent study (H Yamamoto et al. Liver Transplantation 2019; 25: 1561-70) provides data on the outcomes of infants who underwent liver transplantation (LT) in the United Kingdom (King’s College Hospital).

A total of 64 infants underwent LT (1989-2014) at a single institution. The authors compared “extra-small” (XS) infants in the first 3 months of life to “small” (S) who were 3-6 months of age.

Key findings:

  • Acute liver failure was the main indication for LT in the XS group (n=31, 84%) compared to the S group (7, 26%)
  • Hepatic artery thrombosis and portal vein thrombosis were similar in both groups: 5.4% and 10.8% in the XS and 7.4% and 11.1% in the S group
  • Bilary stricture and leakage were similar: 5.4% and 2.7% in the XS and 3.7% and 3.7% in the S group
  • 1-, 5-, and 10-year survivals were 70.3%, 70.3% and 70.3% in the XS group and 92.6%, 88.9%, and 88.9% in the S group (not statistically significant)

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Quebec City, Frontenac Hotel and Boardwalk (early in the day)

Easy Advice for Pediatric Hepatologists: PSC Surveillance Recommendations

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A recent clinical practice update (CL Bowlus et al. Clin Gastroenterol Hepatol 2019; 17: 2416-22) makes several recommendations on surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis (PSC).

Full Text Link: AGA Clinical Practice Update on Surveillance for Hepatobiliary Cancers in Patients With Primary Sclerosing Cholangitis: Expert Review

I will highlight the most important recommendation for pediatric hepatologists:

  • Best practice advice 6: Surveillance for cholangiocarcinoma should not be performed in PSC patients with small-duct PSCs or those younger than age 20.

In the text, the authors note that “in pediatric PSC patients, cholangiocarcinoma is very rare, with only 8 of 781 (1%) …developing cholangiocarcinoma” (MR Deneau et al. Hepatology 2017; 66: 518-27)

Here are the other recommendations:

  • Best practice advice 1  Surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with PSC regardless of disease stage, especially in the first year after diagnosis and in patients with ulcerative colitis and those diagnosed at an older age.
  • Best practice advice 2 Surveillance for cholangiocarcinoma and gallbladder cancer should include imaging by ultrasound, computed tomography, or magnetic resonance imaging, with or without serum carbohydrate antigen 19-9, every 6 to 12 months
  • Best practice advice 3  Endoscopic retrograde cholangiopancreatography with brush cytology should not be used routinely for surveillance of cholangiocarcinomas in PSC.
  • Best practice advice 4  Cholangiocarcinomas should be investigated by endoscopic retrograde cholangiopancreatography with brush cytology with or without fluorescence in situ hybridization analysis and/or cholangioscopy in PSC patients with worsening clinical symptoms, worsening cholestasis, or a dominant stricture.
  • Best practice advice 5  Fine-needle aspiration of perihilar biliary strictures should be used with caution in PSC patients considered to be liver transplant candidates because of concerns for tumor seeding if the lesion is a cholangiocarcinoma.
  • Best practice advice 7 The decision to perform a cholecystectomy in PSC patients with a gallbladder polyp should be based on the size and growth of the polyp, as well as the clinical status of the patient, with the knowledge of the increased risk of gallbladder cancer in polyps greater than 8 mm.
  • Best practice advice 8  Surveillance for hepatocellular carcinoma in PSC patients with cirrhosis should include ultrasound, computed tomography, or magnetic resonance imaging, with or without α-fetoprotein every 6 months.

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From The Onion

 

Using Less Steroids for Autoimmune Hepatitis

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A recent retrospective study (S Pape et al. Clin Gastroenterol Hepatol 2019; 17: 2068-75) with 451 adults (1978-2017) examined outcomes among patients based on steroid dosing.

A high-dose group (n=281) with initial prednisone/prednisolone dose of ≥0.5 mg/kg/day was compared with a low dose group (n=170) <0.5 mg/kg/day.  The low dose group had higher rates of cirrhosis (25.9% vs. 15.3%) but lower median ALT values (7.1 ULN vs. 13.4 ULN) and lower median bilirubin values (48 vs 29 micromol/L).

Key findings:

  • There was no difference in rates of transaminase normalization at 1 year: 76.2% vs 77.6%
  • Transaminase normalization was lower in patients with cirrhosis 58.1% compared to 70.7% with cirrhosis
  • Most patients were receiving low-dose steroids at 6 months, 87.4% in high-dose group compared to 83.5% in low-dose group
  • Cumulative steroid dose was lower in low-dose group, with median of 2573 mg over 6 months compared to 3780 mg

Though, not studied in this report, AASLD has recommended use of immunoglobulin levels may help with immunosuppression titration. The editorial (pg 1948-49) notes that budesonide is another alternative for AIH without cirrhosis, though “long-term outcomes including histologic remission and appropriate tapering strategy for budesonide are currently lacking.”

My take: Particularly in patients without severe inflammation, lower steroid doses can be considered for autoimmune hepatitis.

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Atlanta Botanical Garden

Need Liver, Will Travel (2019)

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A recent study (AJ Kwong et al Clin Gastroenterol Hepatol 2019; 17: 2347-55) quantifies the potential advantage of moving to receive a liver transplant. This had been discussed in 2016 blog post as well (Need Liver, Will Travel)

During the study period (2004-2016), there were 104,914 waitlist registrations.

Key findings:

  • 60.985 patients received a liver transplant during the study period
  • 2930  (2.8%) pursued listing at a distant center
  • Distant listing was associated with a 22% reductinon in the risk of death within 1 year

My take: this study highlights socioeconomic disparity in acquiring a liver transplant along with potential geographic disparities.

Related article:

“Transplantation Traffic –Geography as Destiny for Transplant Candidates” NEJM 2014; 271: 2450-52.  Describes ongoing geographic inequality in organ distribution and obstacles to improving allocation.

Related blog posts:

Botanical Garden,, Chicago