Category Archives: Pediatric Gastroenterology Liver Disease

NAFLD –Analogous to a Dog Chasing A Bus?

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I am not sure of the origin of the expression “what is a dog going to do if it catches a bus?”  However, I am reminded of this expression after reading a recent article about nonalcoholic fatty liver disease (J Pediatr 2014; 164: 707-13).

This retrospective study, “Histologic Abnormalities in Children with Nonalcoholic Fatty Liver Disease with Normal or Mildly Elevated Alanine Aminotransferase Levels,” analyzed 91 children (5-18 years) with suspected NAFLD who had normal or mildly elevated ALT values from 12 U.S. medical centers.  They obtained liver biopsy specimens within 180 days of the ALT measurement and compared them from 392 children with elevated ALT.

When reading this title, one has to wonder, how did they select these children for this study?  First of all the authors used two NASH CRN databases with 483 children.  The reasons for NAFLD evaluation at entry in the current study included symptoms of liver disease in 22%, identification during evaluation of another illness in 38%, routine physical exam (41%), and other causes in 6%. At one point, elevated ALT was evident in 74% and radiographic evidence of steatosis in 55%.

The authors conclude that “liver biopsy specimens from children with NAFLD with normal or mildly elevated ALT levels show significant histological abnormalities, including advanced fibrosis…measurement of ALT may underestimate liver injury in NAFLD.” Yet, while it is true that ALT values may not have adequate sensitivity for liver injury, the authors deploy some circular logic; when one understands the selection of these patients, it comes as no surprise that some had advanced liver findings on biopsy.  If one identifies an abnormal liver on ultrasound and confirms this on liver biopsy, this is targeting a population whose findings are not generalizable.

Outside of a research study, how does one decide which patients will benefit from a liver biopsy? This study does not offer any clarity.

And, if one identifies more cases of NAFLD, what is one to do?  Besides weight loss (which should be recommended already in the majority), there are no other proven treatments.  The associated editorial (pgs 684-86) reminds the reader to use appropriate normative values for ALT (<25.8 U/L for boys and <22.1 U/L for girls).  In the study’s discussion, the lack of consensus among expert recommendations is acknowledged.  Furthermore, in those who have recommended frequent screening with ALT values in obese children, the authors note that “evidence of the utility and cost-effectiveness of this approach is still lacking.”

Another study in the same issue (J Pediatr 2014; 164: 699-706) suggests a possible link between obstructive sleep apnea (OSA) and more advanced liver histology in NAFLD.  This was a cross-sectional study with only 25 patients (88% Hispanic, mean age 12.8 years).  The authors speculate that nighttime hypoxemia triggers oxidative stress and may induce further liver injury.  53% of those with OSA had stage 2 or higher fibrosis compared with only 10% of those without OSA.

Bottomline: NAFLD occurs in a lot of children and a normal or mildly elevated ALT does not exclude more severe disease.  OSA may be either an epiphenomenon or a causative factor for more severe NAFLD findings.

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Withdrawing Immunosuppression with Autoimmune Hepatitis

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A recent retrospective study indicates that withdrawal of immunosuppression in autoimmune hepatitis (AIH) can be successful in carefully selected children (J Pediatr 2014; 164: 714-19).

A cohort of 56 children with AIH were followed for a median of 5.6 years and with a median age of 11 years (62% female).  Demographics noted that cirrhosis was present in 14%, primary sclerosing cholangitis 21%, and AIH type II in 9%.

Key findings:

  • Biochemical remission with immunosuppression was achieved in 76% of all patients at a median of 1.2 years; 23% of these patients experienced a subsequent relapse.
  • Withdrawal of immunosuppression was successful in 14 of 16 of patients with type 1 AIH who had been treated for a median of 2.0 years after diagnosis.
  • When the authors excluded patients with inflammatory bowel disease, they noted that the probability of achieving a sustained immunosuppression-free remission was 42% at 5 years.  Sustained remission was defined as biochemical remission for >1 year, liver biopsy without inflammation, and no relapses.
  • Patients less likely to reach a biochemical remission with immunosuppression included patients with cirrhosis, elevated INR, positive ANCA titer, and patients with coexisting autoimmune disorder.

In their discussion, the authors note that treatment withdrawal is “generally considered more successful after at least 3 years of therapy,” though only 50% of their patients who had therapy withdrawn had been treated that long.  In addition, they state that while coexisting immune disorders often result in more frequent relapses, the one exception in the literature is celiac disease when patients adhere to a strict gluten-free diet.  They also urge all patients diagnosed with AIH to undergo testing for celiac disease and thyroid disease.

Limitations of the study include the following: small numbers of patients, single center (Utah), retrospective design, and cholangiography was not performed uniformly.

Take-home message: In patients doing well with AIH for 2-3 years & with normalized liver histology, it may be possible to withdraw immunosuppression.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

 

Living on MARS

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As anyone who follows this blog knows, I really like good acronyms.  MARS which stands for molecular adsorbents recirculating system is another good one.  Data regarding the use of MARS for acute liver failure (ALF) due to Wilson disease in children has been recently reported (JPGN 2014; 58: 160-64, editorial 140-41).

Background: MARS is a form of dialysis to remove albumin-bound toxins via a specialized membrane. MARS has been studied as a potential bridge to liver transplantation or as a support to try to avoid liver transplantation in some cases.

The present study with only four children is not terribly informative.  However, both the article and the editorial provide references on small randomized controlled trials which concur with the conclusions of the authors that “biological and clinical improvement is demonstrated in the MARS treatment group compared with the standard medical treatment group.”  Yet, recent large multicenter randomized controlled trials are inconclusive with regard to whether MARS improves survival.

Bottomline (from editorial): “MARS does not prevent transplantation, and survival outcome post transplantation is unclear.  There is no robust evidence to justify the financial implications of this intervention in a clinical setting. The present role of MARS remains within the research setting.”

The Liver –Front and Center

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Before proceeding with today’s post, those who read yesterday’s post may be interested in Atul Gawande’s take on the NEJM checklist publication -here’s the link (from Atul Gawande’s twitter feed): bit.ly/1d6v31z. 

A recent review “Extrahepatic Complications of Nonalcoholic Fatty Liver Disease” (NAFLD)(Hepatology 2014; 59: 1174-97) seems to position the liver as the center of a multitude of problems rather than one of many associated problems.

It is known that NAFLD increases the risk of end-stage liver disease and hepatocellular carcinoma.  However, the majority of deaths among individuals with NAFLD are attributed to cardiovascular disease and malignancy.  This lengthy review describes in great detail the associations between NAFLD and the risk of developing cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and colorectal neoplasm.  The presence of NAFLD appears to convey an independent increase in risk for these conditions.

Key points:

  • “The aggregated evidence provides strong evidence that individuals with NAFLD are at increased “independent” risk of developing CVD.  The risk of CVD mortality may be greater in subgroups of subjects with NASH and advanced fibrosis, compared to those with simple steatosis.”
  • “USS-defined NAFLD is associated with a 2- to 5-fold risk of developing T2DM after adjustment of several lifestyle and metabolic confounders.”
  • “NAFLD (in particular, biopsy-proven NASH) is associated with a greater prevalence of CKD (20% to 50% of patients). USS-defined NAFLD carries a 1.5- to 2-fold adjusted risk of incident CKD.”
  • “A true causal relationship between and NASH and colorectal cancer cannot be confirmed.”
  • Other potential extrahepatic manifestations: hypothyroidism, polycystic ovarian syndrome, obstructive sleep apnea syndrome, and osteoporosis.

Take-Home Message: NAFLD has independent associations for greater risk of CVD, hyperglycemia, and malignancy.  Whether these associations are simply an epiphenomenon  of more aggressive metabolic syndrome or whether the liver injury primarily causes these additional risks remains unclear.

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What is the long-term neurological outcome in Tyrosinemia Type 1?

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The answer to the blog post title: mild impaired cognitive function, according to a recent study (J Pediatr 2014; 164; 398-401).

Using a cross-sectional study, children (n=10) with tyrosinemia type 1 were compared with their unaffected siblings.  Intelligence was measured with Wechsler Scales. These children were treated with nitisinone (NTBC).  NTBC which was introduced in 1992 has markedly improved the survival of tyrosinemia by blocking the accumulation of toxic metabolites.  Liver dysfunction is controlled in >90% and the risk of liver cancer has been reduced as well.

Key results:

  • Average IQ score in tyrosinemia patients was lower than their siblings: 71 vs. 91 (P= .008).
  • In the five patients with repeated measurements, there was a gradual decline in IQ over time (240 months), from 96 to 69.

Why?

The authors do not know but speculate that cognitive impairment may have been overlooked previously due to the short life span of untreated patients.  While the lower IQ may be due to the treatment itself, “similarly low IQs in patients who stopped taking nitisone after undergoing liver transplantation argues against the acute toxicity of nitisinone.” Thus, elevated tyrosine/low phenylalanine levels, which occurs in patients on NTBC/restricted protein diet, may be related to cognitive impairment.

Acute Liver Failure –Is There a Role for Steroids?

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The title is not a simple question.

Some who support the use of steroids (for acute liver failure) should remember Galen’s assertion about a different treatment, circa 100 AD:   “All who drink of this remedy recover in a short time except those whom it does not help, who all die. It is obvious, therefore, that it fails only in incurable cases.”

Two recent publications offer conflicting advice about steroids for acute liver failure (ALF):

  • Hepatology 2014; 59: 612-21.
  • J Pediatr 2014; 164: 407-409.

The first study involved a retrospective analysis of autoimmune, indeterminate, and drug-induced ALF from patients (n=361) prospectively enrolled in the ALF Study Group between 1998-2007.

  • Autoimmune, n=66, mean age 46 years
  • Indeterminate, n=164, mean age 39 years
  • Drug-induced, n=131, mean age 44 years

Outcomes:  Steroid use was associated with increased spontaneous survival (35% vs 23%) but this benefit did not persist with multivariate analysis.  In addition, steroid use was associated with lower survival in patients with the highest MELD scores. Furthermore, the authors discount the possibility of selection bias, noting that INR was higher in the no-steroid group.

In contrast, the second article, a case presentation/pediatric grand rounds article, states that “in our experience over the past decade, more than one-half of the children (56%) presenting with indeterminate acute hepatitis or ALF (after being evaluated) comprehensively …had a markedly elevated sIL-2R level (>5000 U/mL) concerning for immune activation but never fulfilling diagnostic criteria for HLH [hemophagocytic lymphohistiocytosis] during their course.”

“Notably, of the patients presenting with elevation of sIL-2R to >5000 U/mL, most who survived with their native liver had received treatment with steroids.” (JPGN 2013; 56: 311-5.) “We propose that children presenting with indeterminate, progressive hepatitis or indeterminate ALF are candidates for prompt initiation of anti-inflammatory therapy when there is concomitant evidence of immune activation.”

In patients with ALF, part of the evaluation needs to include sIL-2R. Other assessments for immune dysregulation would include serum triglycerides, ferritin, “CD107a expression, perforin/granzyme B protein expression, and assessment for macrophage activation (soluble CD163).”

Bottomline: If HLH criteria are not met, but patients have marked elevation of sIL-2R (>5000 U/mL), empiric corticosteroids need to be considered. Perhaps there is a window of opportunity (before a patient develops a high MELD score).  At the same time, we need to acknowledge that our knowledge base remains incomplete and it is unclear whether this will improve the outcome.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.

Teaching an Old Drug New Tricks

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A couple recent articles focused on the new uses of methotrexate (MTX) and how to handle potential hepatotoxicity:

  1. J Pediatr 2014; 164: 231-36
  2. Inflamm Bowel Dis 2014; 20: 47-59

In the first medical review article, the authors note the efficacy of MTX for the following:

  • Juvenile idiopathic arthritis
  • Uveitis
  • Psoriasis
  • Crohn disease
  • Juvenile dermatomyositis
  • Localized scleroderma
  • Vasculitis

This review article discusses mechanism of action which is poorly understood along with pharmacogenomics and practical issues in usage.  The latter includes the need for supplemental folic acid.  Other points:

  • “The long-term safety of MTX is remarkable”
  • “The issue of nausea and vomiting…can be especially disturbing.”  They note that one study demonstrated that ondansetron 1 hour prior to MTX from the first injection prevented nausea, which was often difficult to treat once developed.
  • “Liver enzyme abnormalities occur frequently (up to 30% of patients) but are usually of minimal clinical significance.”  Best to draw blood tests 1-2 days before MTX dosing.
  • “In children, unlike adults, MTX-related pulmonary adverse events are very rare.”
  • “In recent years it was shown that live vaccine boosters are effective and safe during MTX use (caution may be needed if MTX is used with other immunosuppression medications)” Ref: JAMA 2013; 309: 2449–56.
  • “Use during pregnancy or within 3 months of planning pregnancy is contraindicated”

The second article was a systemic review which identified 12 high-quality studies which focused on MTX hepatotoxicity in children.  Key findings:

  • 57 of 457 developed some degree of abnormal liver biochemistries.
  • Due to hepatotoxicity, dose reductions were undertaken in 6.4% and 4.5% discontinued MTX.

The authors note that studies of MTX in adults with IBD have not demonstrated cumulative liver toxicity from MTX.  In addition, many of the patients with hepatotoxicity may have had  other reasons for abnormal liver biochemistries including other medications (eg. glucocorticoids).  “Confirmation of MTX hepatotoxicity with a liver biopsy is seldom performed in children;” as a consequence, the exact rate of MTX hepatotoxicity is unknown.

The authors propose that liver biochemistry monitoring occur at baseline, biweekly x 2, then every 2-3 months.  Also, the authors recommend:

  • If ALT < 2 times upper limit of normal (ULN), check liver biochemistries every 2 weeks
  • If persistent abnormalities, the authors recommend an ultrasound
  • If ALT ≥ 2 times ULN, repeat testing should be obtained and consider consultation with a hepatologist

Bottomline: Methotrexate is an important medication for Crohn disease –there are not very many available.  If there are persistent liver enzyme elevations, dose reduction of MTX (or cessation) may be necessary.  As a practical matter, it is advisable to obtain blood draws 1-2 days prior to MTX rather than afterwards. Nausea can be minimized with ondansetron and weekend dosing.

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HCV Website -No “Cat on The Roof”

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A joke I heard a long time ago:

A guy asks his friend to check up on his cat while he is away on a trip.  He calls to see how kitty is doing.  His friend says, “Sorry but she died.”  In response, he tells his friend, “you should have broken me the news a lot more gently.  Maybe you could have said she was up on the roof and the next time I called it would have been easier to accept the news.”  A few years pass and he again asks his friend for a favor, this time to check up on his grandmother while he is away on a trip.  He calls to see how granny is doing.  His friend says, “Oh, she is up on the roof.”

The AASLD and “the Infectious Diseases Society of America (IDSA), in collaboration with the International Antiviral Society-USA (IAS-USA), announced the launch of a new website,HCVguidelines.org, that offers up-to-date recommendations for testing, managing, and treating hepatitis C virus (HCV) infection.”

The website clearly dismisses the previous established breakthrough treatments of telaprevir and boceprevir “because they are markedly inferior.”

For anyone who has been confused with the onslaught of new work on HCV, the website spells out in clear detail the best regimens for HCV treatment now that both sofusbuvir and simeprevir are available.

Bottomline: The website makes it clear that both telaprevir and boceprevir are up on the roof.

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Magnetic Resonance Elastography for Hepatic Fibrosis Assessment

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This large case series of 35 children indicates that Magnetic Resonance Elastography (MRE) may be quite useful to assess hepatic fibrosis as well as steatosis (J Pediatr 2014; 164: 186-8).

The study (2011-2012) included 27 patients with nonalcoholic fatty liver disease (NAFLD); 22 of this group had probable or definite nonalcoholic steatohepatitis (NASH).  Other diseases included progressive familial intrahepatic cholestasis (type 2), autoimmune sclerosing hepatitis, Wilson disease, glycogenic hepatopathy (due to type 1 diabetes), and other liver conditions.  All of the patients in the study had undergone liver biopsy as well.

The authors showed that MRE had a high accuracy to detect significant fibrosis and may be better suited for severely obese patients.  At the cutoff they identified, the sensitivity was 88% and the specificity 85% for detecting significant fibrosis.

In severely obese patients, alternative imaging techniques, namely transient elastography and acoustic radiation force imaging have higher technical failure rates.  The authors note that at their institution, more than 100 MRE studies have been completed (including many without liver biopsies); thus far, only two morbidly obese patients failed completion.  In addition, the authors state that this limited study costs about twice that of an ultrasound.

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Liver Update: Headlines and Links Only

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  1. From AGA: Hepatic failure flagged as unexpected boceprevir safety signal in adverse event review. GI & Hep News: http://ow.ly/rSCEF 
  2. From NY Times: Spike in Harm to Liver Is Tied to Dietary Aids nyti.ms/JPN9fK 
  3. From Jeff Schwimmer (The Liver Post): First case report of Liver Cancer in a child with Nonalcoholic Fatty Liver Disease. He is only 7 years-old. http://goo.gl/6dJbzs 
  4. “Recurrence of Hepatopulmonary Syndrome Post-Orthotopic Liver Transplantation in a Patient with Noncirrhotic Portal Hypertension” Hepatology 2013; 58: 2205-06.
  5. “Management of Hepatitis B: Our Practice and How It Relates to the Guidelines” Clin Gastroenterol Hepatol 2014; 12: 16-26.  Terrific review and insights.
  6. “Acute Liver Failure” NEJM 2013; 369: 2525-34.
  7. “Cesarean Section Reduces Perinatal Transmission of Hepatitis B Virus Infection from Hepatitis B Surface Antigen-Positive Women to Their Infants” Clin Gastroenterol Hepatol 2013; 11: 1349-55. Retrospective, nonrandomized study -“performing elective cesarean section only in highly viremic mothers with pre-delivery HBV DNA levels ≥1,000,000 copies/mL may be advisable.”

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