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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Joshua Tree National Park

Phase 3 Trial of Sebelipase Alfa for Lysosomal Acid Lipase Deficiency

A recent report (BK Burton et al. NEJM 2015; 373: 1010-20, editorial 1071-1) provides preliminary evidence of efficacy of Sebeliplase Alfa for lysosomal acid lipase deficiency.

In this multicenter, randomized, double-blind, placebo-controlled study of 66 patients, enzyme replacement therapy with Sebelipase alfa was examined (1 mg intravenously every other week).  After 20 weeks, all patients were treated by open-label. Of the 32 patients who had had liver biopsies, 10 (31%) were noted to have cirrhosis.


  • Alanine aminotransferase normalized in 11 (36%) of treated patients compared with 2 (7%) of controls
  • Improvement in lipid levels and reduction in hepatic fat content were evident in treated patients (P<0.001 for all comparisons, except P-0.04 for triglycerides

The editorial provides a schematic explaining how sebelipase alfa targets the hepatocyte (Figure 1).  The authors note that “longer-term follow-up in a larger number of patients will be required for confirmation.”

Related blog post:

Lysosomal Acid Lipase Deficiency -Another Needle in a Haystack

A recent article (Atherosclerosis 2014; 235: 21-30) reviews lysosomal acid lipase deficiency (LAL-D) and how this rare disease needs to be considered by pediatric hepatologists.

LAL-D is a rare lysosomal storage disease which encompasses a rapidly progressive disease in infants (previously referred to as Wolman disease) as well as a later-onset condition called cholesteryl ester storage disease (CESD).  Both of these diseases are caused by mutations in the LIPA gene and share the same pathophysiology related to deficiency of LAL. The disease prevalence estimates vary widely (1 in 40,000 to 1 in 300,000) and depend on ethnicity and location.  Jewish, Iraqi, and Iranian infants appear to be at highest risk.

According to the review algorithm, patients with three or more of the following should be considered for screening:

  • ALT >1.5 ULN
  • Hepatomegaly (may be mild)
  • HDL <50 mg/dL
  • Low BMI (in adults <30 kg/m2)
  • Liver biopsy with microvesicular steatosis; grossly the liver may appear orange

Thus, the potential target patients:

  1. Non-obese individuals with persistent increases in LFTs –usually with LDL >160 and low HDL <50
  2. Non-obese NAFLD/microvesicular steatosis

Given the potential for treatment with recombinant sebelipase alfa (Synageva Biopharma) and the widely available testing, looking for LAL-D makes sense in selected patients; though, even in highly selected patients, finding cases may truly be like finding the so-called ‘needle in a haystack’ given the huge numbers of individuals with elevated ALTs who do not have LAL-D.

Note: many of the review’s authors received research grants from Synageva.  (I do not have any financial conflicts to disclose.)