Bad Fatty Liver Disease Can Get Worse Quickly

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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Outcomes of Liver Transplantation in Small Infants

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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Easy Advice for Pediatric Hepatologists: PSC Surveillance Recommendations

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.

Using Less Steroids for Autoimmune Hepatitis

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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Need Liver, Will Travel (2019)

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.

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How Reliable is an Acetaminophen Level in Patients with Acetaminophen Overdose?

A recent study (TM Leventhal et al. Clin Gastroenterol Hepatol 2019; 17: 2110-6) provides more data indicating that acetaminophen levels are frequently undetectable even in patients suspected of developing acute liver failure (ALF) due to acetaminophen overdose.

The authors performed a retrospective study with 434 subjects from the ALF study group who met criteria for either ALF (coagulopathy and hepatic encephalopathy w/in 26 weeks of first symptoms) or Acute Liver Injury (ALI) (severe liver injury with coagulopathy but no encephalopathy).  In this group, all of the patients had liver disease attributed to acetaminophen (APAP) toxicity.

Key findings:

  • 227 patients (52%) had undetectable acetaminophen levels
  • Transplant-free survival rate was 79.5% (including both ALF and ALI patients)
  • APAP-protein adduct data was available for 37 patients in cohort; all patients with this assay had evidence of APAP toxicity regardless of whether APAP level was detected

Discussion Points:

  • Symptoms from APAP toxicity frequently emerge >24 hours after ingestion.  APAP, though, has a short half-life, approximately 2-2.5 hours.  Thus, most patients will have APAP clearance from plasma in 18 hours
  • Unintentional overdose, often with multiple doses over therapeutic limit of 4 g/day (in adults), more frequently is associated with an undetectable APAP level than a single large intentional overdose which results in a higher peak level

My take: This study shows that APAP levels are unreliable in determining APAP ingestions and not predictive of ALF.  The use of N-acetylcysteine should not be determined by APAP levels in patients with suspected overdose.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

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Improving Fatty Liver Disease Nomenclature

Those who follow this blog regularly know that I have frequently agreed with articles suggesting improving/updating nomenclature for many conditions including the following:

A recent commentary (M Eslam et al. Gastroenterol 2019; 157: 590-3) suggests that fatty liver diseases could use a nomenclature makeover as well.

In pediatrics, the issue of alcoholic and nonalcholic fatty liver disease (NAFLD) overlap is fairly minor in many ways.  In fact, when I am seeing a young teen with NAFLD, parents will often chuckle when I tell them that ‘Johnny’ needs to lay off the booze (now and in the future).  However, it is difficult to fully differentiate nonalcoholic fatty liver disease from alcoholic fatty liver disease, especially in adults.

Full Text: Toward More Accurate Nomenclature for Fatty Liver Diseases

Key points:

  • “Light (1.0-9.9 g/d) or moderate (10.0–29.9 g/d; 10.0–19.9 g/d for women) alcohol consumption in patients with NAFLD is not uncommon…The negative impact of alcohol intake also extends to nonalcoholic steatohepatitis resolution.”
  • “it is time for clinicians to recognize that, within the spectrum of fatty liver disease, there will be patients with true alcohol-related liver disease (AFLD), those with predominant AFLD compounded by metabolic cofactors, those with true NAFLD in whom alcohol consumption is near zero and disease progression is due to metabolic factors, and perhaps a majority with fatty liver disease owing to an abnormal metabolic milieu but with alcohol intake of ≤30 g/d.”
  • ” An updated and more appropriate nomenclature and classification system is required to reflect the nuances of disease etiology within the spectrum of fatty liver disease…”
    • MPFL: metabolic dysfunction predominant fatty liver;
    • APFL, alcohol predominant fatty liver;
    • MPFL/A and MPFL/N: metabolic dysfunction predominant fatty liver with, and without alcohol intake that is anything more than ceremonial
    • APFL/M and APFL/N: alcoholic predominant fatty liver with metabolic dysfunction or with no metabolic dysfunction.

My take: The authors present a good rationale for updating fatty liver disease –will this be adopted?

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