More Data, More Nuance with MMP-7: Best Biliary Atresia Biomarker

As noted by my previous blog (New Way to Diagnose Biliary Atresia), I am enthusiastic about the development of MMP-7 (Serum Matrix Metalloproteinase-7) as a biomarker for biliary atresia.

A new study (Wu J-F , Jeng Y-M, Chen H-L, Ni Y-H, Hsu H-Y, Chang M-H. Quantification of serum matrix metallopeptide 7 levels may assist the diagnosis and outcome prediction for biliary atresia. J Pediatr. 2019;208:30–7) and associated editorial provide additional data and nuance.

Key points:

  • “Wu et … studied 100 cholestatic infants presenting consecutively to their institution over a 10-year period, including 36 eventually diagnosed with biliary atresia. Median serum MMP-7 levels were significantly higher in biliary atresia at the time of diagnosis, with an optimal serum MMP-7 level of >1.43 ng/mL for predicting biliary atresia.  In comparison, similarly high MMP-7 levels were found in only 1 infant who was cholestatic without biliary atresia.”
  • “The authors found that serum MMP-7 levels were significantly lower in the 14 infants ≤30 days old diagnosed with biliary atresia, compared with the 22 infants >30 days old at diagnosis. In some cases, serum MMP-7 levels in younger infants with biliary atresia overlapped with those from infants with other liver diseases, such as neonatal hepatitis.”
  • After Kasai portoenterostomy: “Serum MMP-7 levels were significantly higher 6 months post-Kasai portoenterostomy in infants who later required liver transplant, with a serum MMP-7 level of >10.30 mg/dL optimally predicting transplant 3-4 years after Kasai portoenterostomy … serum MMP-7 levels are still high even in patients who do not need liver transplant.”
  • The authors “highlight 1 complication with using serum MMP-7 levels: values can vary widely among different enzyme-linked immunosorbent assay kits used.”

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How Often Do Children with Obesity Have a Fatty Liver?

According to a recent study (EL Yu et al. J Pediatr 2019; 207: 64-70), about one-third of boys and one-fourth of girls with obesity have nonalcoholic fatty liver disease (NAFLD).

This study from San Diego with 408 children aged 9-17 years (mean 13.2 years) with obesity evaluated for NAFLD with laboratories (to exclude other etiologies) and with liver MRI proton density fat fraction (PDFF), with ≥5% considered the threshold for NAFLD.

Key findings:

  • Prevalence of NAFLD was 26% in this population, with 29.4% in males and 22.6% in females
  • The optimal cut offs of ALT for detecting NAFLD in this study were ≥30 U/L for females and ≥42 U/L for males. These are much lower than NASPGHAN guidelines which proposed ≥80 U/L or twice the ULN as thresholds for further investigation.  (The NASPGHAN recommendations are likely to have higher specificity in identifying children at greater risk for nonalcoholic steatohepatitis (NASH).)

Limitations:

  • 77% of this cohort were hispanic, thus prevalence may vary significantly in other populations.
  • MRI-PDFF -the exact cut off is unclear.  The authors note that if 3.5% were chosen, the NAFLD prevalence jumped to 49.3% (according to Table II –though the discussion stated 53.2%)

My take: Understanding the likelihood of NAFLD in children at risk is a helpful first step.  This study points to the growing use of non-invasive diagnosis with MRI.

On a related topic, briefly noted: “Obesity in Adolescents and Youth: The Case for and against Bariatric Surgery” (A Khattab, MA Sperling. J Pediatr 2019; 207: 18-22). In this review, the authors refer frequently to endocrine society guidelines (J Clin Endocrinol Metab 2017; 102: 709-57).    These guidelines generally recommend bariatric surgery only under specific conditions (eg. completion of Tanner 4 or 5 along with a BMI of 40 kg/m-squared or BMI of 35 with significant extreme comorbidities after failure of lifestyle modifications & without untreated psychiatric illness).  This review predicts increasing use of bariatric surgery in adolescents “as more data on long-term outcomes in larger cohorts become known.”

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New Way to Diagnose Biliary Atresia

Case report: Recently, our group consulted on a 3 week old infant (ex34 week) who weighed 2.8 kg and had cholestasis. In addition, he had a GGT in the 400s and an ultrasound notable for a “small” gallbladder.  Due to the patient’s small size, he underwent a HIDA (no excretion).   The GGT was actually improving but the clinical situation was concerning for biliary atresia.

Instead of arranging a liver biopsy, we were able to perform a MMP-7 (Serum Matrix Metalloproteinase-7) assay which will be commercially available soon.  The result, which returned in 48 hours, indicated that the child had a >95% likelihood of biliary atresia. Subsequently, this infant is recovering from a hepatoportoenterostomy. No liver biopsy was needed prior to surgery.

My take: The MMP-7 assay is a remarkable test which is going to rapidly change the approach to infants with cholestasis.  I expect that this test will be ordered along with a serum alpha-one antitrypsin phenotype and an ultrasound.  In those with persistent cholestasis with negative initial testing, it is likely that, in the majority, a genetic cholestasis panel would be pursued rather than a liver biopsy.

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Celiac Hepatopathy 2019

A recent retrospective study (E Benelli et al. JPGN 2019; 68: 547-51) examines a large cohort of patients (=700) who were diagnosed with celiac disease (CD) from 2010-2016 and had available liver transaminases.

Key findings:

  • ALT values >40 U/L were elevated in only 3.9% (27/700)
  • Younger age (<4.27 years) correlated with a higher risk of liver involvement with OR 3.73
  • Of these 27 patients with elevated ALT, 18 had adequate followup.  All but 3 patients normalized ALT values after at least 1 year; of these, 1 was diagnosed with sclerosing cholangitis. In the other two, one was thought to be nonadherent with gluten-free diet and one had dropped ALT to 47 U/L.
  • Thus, definitive autoimmune liver disease was identified in only one patient

My take: This study shows a lower rate of liver involvement than previous studies.

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Liver Shorts April 2019

CL Mack et al. JPGN 2019; 68: 495-501. This multicenter prospective open-label phase I/III trial of IVIG in biliary atresia patients status-post Kasai indicated that the infusions were tolerated.  However, though this study was not powered to detect efficacy, survival with native liver was LOWER among patients who had received IVIG (n=29): 58.6% compared to the comparison placebo group 70.5% (n=64).  Thus, despite the theoretical advantages of IVIG which targets aspects of the immune system and improvement in a murine model, in practice IVIG does not appear promising for biliary atresia.

D Kim et al. Hepatology 2019; 69: 1064-74. This study shows that despite improvements in hepatitis C mortality rates associated with newer treatments, there is an overall increase in mortality rates from cirrhosis and hepatocellular carcinoma.  This increase is driven by increasing prevalence and severity of both alcoholic liver disease and nonalchoholic fatty liver disease. The overall cirrhosis-related mortality increased from 19.77/100,000 persons in 2007 to 23.67 in 2016 with an annual increase of 2.3%. Similarly, the overall HCC-related mortality increased from 3.48/100,000 persons in 2007 to 4.41 in 2016 at annual increase of 2%. The editorial on page 931 (TG Cotter and MR Charlton) notes that each year there are more than 40,000 deaaths associated with chronic liver disease.

H Park et al. Hepatology 2019; 69: 1032-45. This study, using Truven Health MarketScan Cata, examined the outcomes of more than 26,000 patients with newly-diagnosed hepatitis C virus (HCV) infection.  Among the 30% who received oral direct-acting antiviral (DAA) therapy, there were improved outcomes in those with and without cirrhosis. In those with cirrhosis (n=2157), DAA was associated with a 72% and 62% lower incidences of HCC and DCC [decompensated cirrhosis] respectively. In noncirrhotic HCV patients (n=23,948), DAA was associated with a 57% and 58% lower incidence of HCC and DCC respectively.  In addition to improved health outcomes, DAA treatment resulted in decrease health care costs, especially for patients with cirrhosis.

Z Kuloglu et al. JPGN 2019; 68: 371-6.  In this multicenter Turkish study, the authors identified 810 children (median age 5.6 years) with unexplained transaminase elevation (62%),unexplained organomegaly (45%), obesity-unrelated liver steatosis (26%) and cryptogenic fibrosis or cirrhosis (6%).  LAL-D [lysosomal acid lipase deficiency] activity was deficient in 2 siblings (0.2%); both had LDL ~155.  Overall, even in at risk groups, LAL-D is rare.

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Best Predictor for Mortality from Biliary Atresia Liver Transplantation Candidates –Cardiomyopathy?

Briefly noted: A recent study (NM Gorgis et al. Hepatology 2019; 69: 1206-18, editorial 940-2 by Elizabeth Rand) indicates that cirrhotic cardiomyopathy (CCM) is very important factor for survival for biliary atresia (BA) patients requiring liver transplantation.

CCM was defined based on two-dimensional echocardiographic criteria: LV mass index ≥95 g/meter-squared or relative wall LV thickness of LV ≥0.42.

Key points:

  • Overall, 11 of 69 patients died, 4 while awaiting liver transplantation and 7 following transplantation.
  • 34 of 69 BA patients in this cohort had BA-CCM
  • All 11 who died had BA-CCM compared with no deaths in the 35 patients without CCM.

My take: Severe BA-CCM needs to be examined further; if severe, it may merit changing allocation policy.

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Biliary Atresia and Bile Lakes

A retrospective study (DA Ginström et al. JPGN 2019; 488-94) review cholangitis associated with biliary atresia and the role of bile leaks.  This study encompasses a ~30 year period (1987-2016) and 61 patients.

Key findings: 

  • 54% had survived with their native liver at a median of 7.3 years; 28 (46%) had ≥ 1 cholangitis episodes/year
  • Cholangitis bouts were >5 times higher among patients with bile lakes
  • Management of bile lakes after 1995 (n=6) was with operative intestinal drainage (bile-lake jejunostomy) which resulted in disappearance or regression of bile lakes in all patients.  Associated with this, yearly cholangitis bouts decreased from 8.8 (4.2-14) to 1.1 (0.2-3.2). Prior to 1995, two patients were managed with PTCD; both died within one year.
  • Among patients who had surgical drainage of their bile lakes, 4 have survived jaundice-free and 2 received liver transplants at 1.3 and 4.9 years after intestinal drainage.

My take: This report provides insight into the management of bile lakes (also referred to as intrahepatic biliary cysts) indicating that bile-lake jejunostomy is effective in symptomatic patients.

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