Background: Transient elastography may help identify patients at greater risk for advanced fibrosis but there is a significant overlap between fibrosis stages and values with transient elastography. In some conditions, like fatty liver, elastography may be less helpful than in others (eg. chronic viral hepatitis).
A recent study (J Pediatr 2018; 198: 84-9) examined the results of transient elastography in 267 children (97 for calibration, 170 for validation) between 2006-2016. The median age was 13 years. Liver diseases included autoimmune (21%), viral (19%), fatty liver (11%), cholestatic (9%), primary sclerosing cholangitis (9%) and post-transplantation (12%).
- Cut points to discriminate F3-F4 and F4 were >8.6 kPa and >11.5 with 81% and 84% accuracy, respectively in calibration cohort
- To discriminate F3-F4 and F4 in validation cohort, these cut points, >8.6 kPa and >11.5, had accuracy of 67% and 75% respectively
Figure 2 provides much greater detail in the typical values for each Metavir stage. For example, in the calibration cohort, the median values and range were the following:
- F0 6.0 (3.2-12.4)
- F1 6.2 (3.2-75)
- F2 5.8 (2.5-52.7)
- F3 10.3 (4.9-32.6)
- F4 20.5 (5.9-68.1)
In the validation cohort, values were similar:
- F0 6.2 (3.0-75.0)
- F1 7.1 (3.3-31.6)
- F2 7.1 (2.5-52.7)
- F3 9.6 (4.4-75.0)
- F4 20.8 (6.8-75.0)
My take: Elastography in measuring liver stiffness is a lot like checking a CRP for inflammatory bowel disease. That is, it can be helpful but cannot be relied on the same way as many radiographic tests (eg. CT scans for appendicitis).
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Moraine Lake, Banff
Obeticholic acid, a Farnesoid X Receptor Ligand, is being studied as a potential agent in nonalcoholic steatohepatitis (NASH). According to a recent study (Lancet 2015; 385: 956-65), patients assigned to receive obeticholic acid were more likely to have improved liver histology compared with placebo (50/110 [45%] compared with 23/109 [21%]). The obeticholic group had increase serum cholesterol and LDL cholesterol. This study looked at a subgroup of patients in the FLINT study who had undergone liver biopsies.
E Vilar-Gomez et al. Gastroenterol 2015; 149: 367-78. This prospective study of 293 patients with histologically-proven NASH were followed after undergoing lifestyle changes for 52 weeks. At week 52, 88 subjects (30%) had lost ≥5% of their weight. Degree of weight loss was independently associated with improvements in all NASH-related histologic parameters (steatohepatitis, NAS activity score, and fibrosis.
G Lassailly et al. Gastroenterol 2015; 149: 379-88. Between 1994-2013, 109 morbidly-obese patients with histologically-proven NASH underwent bariatric surgery. One year after surgery, NASH had disappeared from 85% of the patients.
P Angulo et al. Gastroenterol 2015; 149: 389-97. In this retrospective analysis of 619 patients with NAFLD (1979-2005), the authors noted that “fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events.”
A recent study (Hepatolology 2014; 60: 1920-8) shows that magnetic resonance (MR) elastography can be an accurate noninvasive tool to assess liver fibrosis.
Background: Assessing severity of liver fibrosis provides important prognostic information in patients with nonalcoholic fatty liver disease (NAFLD); however, these patients are often obese which decreases the success of transient elastography. In addition, high hepatic fat content may alter the results of transient elastography. Hence, an alternative noninvasive technique is desirable.
Design: Prospective study with 117 consecutive patients with biopsy-proven NAFLD who also underwent 2D-MR elastography between 2011-2013.
- Fibrosis stage: stage 0 n=43, stage 1 n=39, stage 2 n=13, stage 3 n=12, stage 4 n=10.
- MR elastography identified stage 3-4 with an accuracy of 0.92, with little overlap between advanced (F3-4) and non-advanced (F0-2) values. The specificity, sensitivity, positive/negative predictive values, and cutoff values are detailed in Table 2.
- Figure 3 provides a cool picture demonstrating the different MR elastography stiffness heat maps correlated with liver fibrosis. Link to similar web-based image from Siemens.
Bottomline: This technology allows a noninvasive measure of liver fibrosis in NAFLD patients and will probably be of use in other liver conditions. Given the fact that a liver biopsy is more risky and often expensive, this technology and other noninvasive markers of advanced liver disease will be important tools.
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Preventing Perinatal Transmission of Hepatitis B Virus (HBV): Hepatology 2014; 60: 468-76. This nonrandomized study, conducted between 2009-2011 with approximately 700 patients, showed that the rate of perinatal transmission of can be brought down almost to zero by instituting therapy with either telbivudine or lamivudine in the third trimester of pregnancy. The accompanying editorial (pgs 448-51) indicates that either telbivudine or tenofovir (both pregnancy class B agents with regard to teratogenicity) are preferred agents due to higher barrier to resistance. And, the article suggests starting as early as week 28 (especially if high viral HBV DNA load) and no later than 32 weeks gestation. Other recommendations from editorial include stopping antiviral after delivery in women who intend to breastfeed.
More on coffee: Hepatology 2014; 60: 661-69. Coffee but not tea conferred protection from cirrhosis mortality. “Compared to non-daily coffee drinkers, those who drank two or more cups per day had a 66% reduction in mortality risk.” This study also had an accompanying editorial (pg 464-67) which reviews the biologic plausibility and potential mechanisms.
NASH pathology: Hepatology 2014; 60: 565-75. The study describes a more precise way to categorize the diagnosis of nonalcoholic steatohepatitis (NASH) using the European Fatty Liver Inhibition of Progression (FLIP) pathology consortium proposal. The diagnosis of NASH requires the presence of ballooning and lobular inflammation in addition to steatosis. Using the FLIP approach, diagnosis concordance increased significantly.
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Many have advocated for the use of parenteral fish oil lipids like Omegaven which are rich in omega-3 polyunsaturated fatty acids (O3FAs), though the data in support of them are limited (New lipid emulsions — lacking data to support usage …).
A recent study (J Pediatr 2014; 165: 59-64) identified seven liver-inclusive intestinal transplants who had received O3FAs. This retrospective review study took place between 2003-2012. These seven patients had received O3FAs for a mean of 62% of their total life span before transplant. While these patients almost all had resolution of cholestasis (mean total bilirubin 0.7 mg/dL at time of transplant), advanced fibrosis (stage 3 or 4) was noted on explant pathology. The histologic inflammatory scores were lower (P=.056) in comparison to O6FA group.
The authors make several important points:
- The “results provide additional evidence that the improvement in hyperbilirubinemia following O3FA substitution therapy does not consistently produce histologic recovery of the liver.”
- This study does not address whether comparable improvements could have been obtained from lipid restriction among the O6FA group.
- Only 1 of 20 studies of O3FA lipid emulsion in PNALD includes hepatic histopathology as an outcome measure.
This is not the first study that indicates that liver fibrosis may persist and progress on O3FA therapy (J Pediatr 2010; 156: 327-31, J Pediatr Surg 2010; 45: 95-9, JPGN 2013; 56: 364-9).
Bottomline: Continued investigation of O3FA emulsions in PNALD is needed and assessing liver histology may be needed prior to intestinal transplantation.
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A retrospective study (Hepatology 2013; 58: 1580-86) of liver biopsies from treatment-naive children enrolled in the PEDS-C study confirm the perception that hepatitis C histologic progression is typically slow.
This study examined 35 pediatric patients (84% genotype 1) who had at least two liver biopsies more than a year a part at eight different centers. For this study, all of the liver histology was scored by a single pathologist. Mean age at first and final biopsy were 8.6 and 14.5 years. Mode of transmission: 57% vertical and 39% transfusion.
- Inflammation was minimal in about 50% at both timepoints.
- Fibrosis was absent in 16% at both timepoints. Fibrosis was limited to portal/periportal in 73% at first biopsy and 64% at second.
- Proportion of patients who had bridging fibrosis/cirrhosis at second timepoint increased from 11% to 20%. Overall, 29.5% (n=13) showed an increase in severity of fibrosis.
- In aggregate, “this cohort did not show significant histologic progression of liver disease over 5 years.”
Implications for treatment per authors: “It may be argued that treatment of a slowly progressing disease in an asymptomatic child may be deferred given the side effects and limitations of the currently available therapy. On the other hand, some might favor early treatment…a liver biopsy …may influence decisions regarding therapy.”
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It takes a long time, even when there is no longer biochemical evidence of parenteral nutrition-associated liver disease (PNALD). A recent study provides long-term data from a population-based, cross-sectional study on liver histology from pediatric intestinal failure (IF) patients (Hepatology 2013; 58: 729-38). Patients were followed from 1984-2010. IF was defined as having either >50% small bowel resection or need for PN >30 days.
The 38 IF participants had a median age of 7.2 years. 16 remained on PN after 74 months (range 2.5-204), 22 had weaned off PN 8.8 years (range 0.3-27) earlier after an average of 35 months of PN exposure.
- Abnormal liver histology was present in 94% of patients on PN and 77% off PN.
- Nearly 60% of patients on long-term PN had significant or severe fibrosis (Metavir stage ≥2).
- Significant liver fibrosis and steatosis persisted after weaning off PN. That is, “liver histology remains abnormal up to 9 years after weaning off PN in the majority of IF patients.”
- One patient off PN developed esophageal varices.
- Risk factors for increased fibrosis: extensive small intestinal resection, (P=.002) loss of ileocecal valve (P=.048), and recurrent sepsis (P=.002).
Bottomline: While there have been important clinical advances in the management of IF, the data from this study indicate that many patients who have normal liver biochemistries continue to have abnormal liver histology. Whether this will have an important clinical impact is not known.
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Much of hepatology relies on surrogate markers to convey whether treatments are effective. For hepatitis B virus (HBV), some of these markers include serology (eg. development of HBV e antibody), improvements in biochemistry (eg. transaminases) as well as histology. Of these, improved histology is likely to have the most bearing on clinical outcomes like progression to end-stage liver disease and hepatocellular carcinoma. A previous study of lamivudine has indicated that regression of fibrosis can reduce the rate of hepatocellular carcinoma (NEJM 2004; 351: 1521-31).
As such, the results of long-term use of agents like tenofovir have been awaited. Since tenofovir along with entecavir are considered 1st line agents, their use has become commonplace for the treatment of HBV. Now 5-year data are available in a large cohort (Lancet 2013; 381: 468-75).
The data from this study was derived from an open-label cohort that followed 48-week double-blind comparison trials. 489 patients completed 240 weeks of treatment. 348 patients had biopsy results available at baseline and at week 240.
- 304 (87%) of those with biopsies at study completion had histologic improvement.
- 176 (51%) had regression of fibrosis
- 71 of 96 (74%) who had cirrhosis at baseline no longer had cirrhosis (≥1 unit decrease in Ishak fibrosis score)
- 3 of 252 without cirrhosis at baseline progressed to cirrhosis at week 240
- No evidence of resistance to tenofovir was evident. Nearly all patients on tenofovir had undetectable HBV DNA
- Adverse safery events were rare
As with all studies looking at liver histology, there were limiting factors including potential sampling errors and variable interpretation. The authors sought to minimize this by using an independent pathologist. Another strength of the study was the broad range of patients to make these findings broadly applicable.
Take-home message: Tenofovir treatment for 5 years is safe and effective. Long-term suppression of HBV can lead to regression of fibrosis and reversal of cirrhosis.
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As survival has improved with liver transplantation (LT), long-term health outcomes have become more important. Reported 5-year survival rate after pediatric LT in North America is >85%. More data on long-term health consequences are provided in a review of 167 10-year survivors from a North American Database (Studies of Pediatric Liver Transplantation –SPLIT) (J Pediatr 2012; 160: 820-6).
Ng VL et al report on frequency of comorbidities as well as quality of life. Of the 10-year survivors who were included in this study: 85 (50.9%) were transplanted in the first year of life; 69 (41.3%) received transplants between 1-7.9 years. Biliary atresia accounted for 55.1% of the transplanted cohort; the remainder were due to the following: metabolic liver disease 23 (13.8%), acute liver failure 18 (10.8%), other cholestatic conditions 17 (10.2%), tumor 6 (3.6%), and other 11 (6.6%).
First allograft survival rates were 94% at 1 year and 88% at 10 years. Health-related quality of life (HRQOL) as assessed by the PedsQL 4.0 Generic Core Scales revealed lower patient self-reported total scale scores for LT survivors compared with healthy children (77.2 vs 84.9, P<.001). 14% had HRQOL >2 SDs below that of a matched healthy population. Other specific post-LT morbidities included the following:
- Impaired linear growth (23% <10th percentile); ongoing steroid therapy was associated with increased risk of poor linear growth.
- Renal dysfunction (9%) –defined as calculated glomerular filtration rate <90 mL/min/1.73 m2.
- Hyperlipidemia: 20% with hypercholesterolemia, and 26% with hypertriglyciridemia
- Lymphoproliferative disease (5%). EBV seroconversion occurred in 46 (47%) of 97 who had been EBV-negative prior to LT. 25 (15%) developed symptomatic EBV infection.
- School performance: 32 (23%) had repeated a grade or were held back at least 1 school year.
- Liver fibrosis: at 10 years, elevated aminotransferases were noted in 11% and increased gamma gluatmyl transpeptidase in 15%. Previous studies from SPLIT indicate fibrosis is common in long-term survivors even with good clinical outcomes.
Alive and well? While survival has improved remarkably, better outcomes are still needed.
Picking winners and losers with liver transplantation allocation
Good care 24/7
Big gift, how much risk
- -Pediatrics 2008; 122: 1128-35. Outcomes of 461 pediatric LT.
- -Am J Transplant 2008; 8: 2506-13. Improving long-term outcomes of LT.
- -Hepatolog 2009; 49: 880-6. LT-Liver fibrosis at 10 year followup.
- -JPGN 2008; 47: 165. ~50% below 1.3 SD of adult height. Many show partial catch up growth.
- -Liver Transplant 2006; 12: 1310. Review article on nutrition for OLTx patient.
Green tea and coffee have a lot of advocates and a number of articles suggest that each can have beneficial effects for the liver. This month’s Hepatology describes how a green tea component, epigallocatechin-3-gallate (EGCG), inhibits hepatitis C viral (HCV) entry. ECGC acts by blocking viral attachment to target cells with all HCV genotypes; it does not affect viral replication. Other components of green tea do not have this effect. A complete description of green tea components is described in the discussion of the article, Hepatology 2012: 54: 1947-55. Also, there have been preliminary dosing studies in healthy volunteers which have shown that EGCG is safe at doses of 800mg daily for four weeks. This would be the equivalent of drinking 8-16 cups of green tea per day (Clin Cancer Res 2003; 9: 3312-19). In order to eliminate HCV, however, even higher amounts of EGCG would be likely.
Coffee also has been studied and has been associated with decreasing liver fibrosis. In addition, coffee may enhance response to HCV treatments. To my knowledge, there have not been extensive studies of either coffee or green tea for pediatric patients.
- -Gastroenterology 2011; 140: 1961. Coffee (3 cups/day) increases response to PEG/RBV in HCV
- -Hepatology 2009; 51: 201. Coffee decreases fibrosis. n=177.
- -Hepatology 2009; 50: 1360. Coffee intake associated with slower progression of HCV liver disease
- -Hepatology 2009; 50: 970. Coffee -2 cups per day decreases risk of liver fibrosis & HCC. Coffee has methylxanthin which inhibits connective tissue growth factor.