Category Archives: Pediatric Gastroenterology Liver Disease

Optimizing lipids to minimize cholestasis

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As discussed in previous blog entries (PNAC, PNALD, and IFAC, More on PNAC, Four advances for intestinal failure), the right amount of lipid and the type of lipid both can contribute to parenteral nutrition associated cholestasis (PNAC).  More information about SMOFlipid which is a complex mixed-type lipid emulsion derived from soybean, coconut, olive, and fish oils is available (JPGN 2012; 54: 797-802).  SMOF contains 30% soybean oil, 30% MCT, 25% monounsaturated fatty acids, and 15% fish oil.

This study had a retrospective cohort comparison design & examined serum bilirubin over 6 months in children with PN-associated cholestasis (PNAC).  In one cohort, 8 patients received the SMOFlipid and the other 9 patients continued on Intralipid (IL).

The SMOF cohort was receiving 81% of caloric needs as PN at entry whereas the IL cohort was receiving 92%.  Six months later, SMOF cohort was receiving 68% of caloric needs as PN compared with 50% for IL cohort.  Nevertheless, the SMOF group had improved cholestasis with a median bilirubin drop of 99 μmol/L compared with an increase of 79 μmol/L among IL patients.  Overall, 5 of 8 children in the SMOF group had resolution of jaundice compared with 2 of 9 in the IL group.

While the authors state that SMOF may have important properties to prevent PNALD, the study has limited ability to draw any firm conclusions.

The authors state that no other treatment innovations were introduced; however, the authors overlook the large discrepancy in lipid volume administered.  The IL group was receiving much more lipid both before and during study.  Prior to entry of study, the IL group was receiving about 3.1 g/kg/day whereas the SMOF group about 2 g/kg/day; the SMOF group continued initially at the same lipid dosing with the new formulation.  This is one of the problems with historical controls.  While the authors might believe that the cholestasis improved because of the lipid content, the key factor may in fact be the amount of lipid given.

In the same issue (JPGN 2012; 54: 803-11), specific plant sterols (PS) were elevated among neonates with intestinal failure-associated liver disease (IFALD).  This study looked at 28 neonates and 11 children from Finland who required PN for more than 28 days.  Specific markedly-elevated PS included stigmasterol, sitosterol, avenasterol and campesterol (Table 4 in study).  Some of these PS in the neonates were more than 20-fold higher than healthy controls.

Lessons about HBV in NYC

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Hepatitis B infection remains a leading cause of cirrhosis and liver cancer worldwide.  In the U.S., the prevalence is estimated at 0.3-0.5% of the population.  An updated look at the epidemiology comes from NYC (MMWR 2012; 61: 6-9).  Investigators randomly selected 180 HBV cases (2008-2010) and investigated them.

Findings/take-home points:

  • Two-thirds were Asian.
  • In 70%, the clinician did not know any of patient risk factors
  • In 62%, the clinician did not know hepatitis A vaccination status (despite recommendations)
  • Main reasons for testing: 27% birth country prevalence, 12% elevated liver tests, 2% hepatitis signs/symptoms
  • Only 75% received counseling regarding transmission

As a result of this investigation, the department of health initiated multiple changes:

  • Clinicians were contacted regarding HAV vaccinations
  • Booklet for patients developed: How to Tell Others You Have Chronic Hepatits B
  • Patient education booklet developed: Hepatitis B: the Facts

These booklets (in five languages) can be ordered in bulk and free of charge within NYC and also online at

Hepatitis B The Facts, Eng.qxp:For Internet, 5.5×8.5 – NYC.gov

Hep B Guide to Telling 7 11_Hep B Chronic – NYC.gov

Other useful links:

DO YOU NEED A HEPATITIS B TEST? – NYC.gov

Unrelated link -but worth a look (thanks to Larry Saripkin for showing me this useful training video):

“dont go ninjin nobody that dont need ninjin” Kung Fu Hillbilly – Training Video – YouTube

Liver biopsy risk in children

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A recent retrospective study from Oslo looks at risk factors and safety of liver biopsy (JPGN 55: 82-87).

Among 190 patients who underwent 275 ultrasound-guided liver biopsies (interventional radiology), there were four major complications –two were due to post-biopsy bleeding, one was due to variceal bleeding within 12 hours, and one was due to the development of pain/acidosis, and tachycardia.  28 patients had minor bleeding.   There were no mortalities, though one patient dropped hemoglobin in half (11.6 to 5.3).

In their patient population, the following had increased risk for major complications:

  • Focal space-occupying lesion/tumor (n=25) OR 2.84  for all bleeding risk; patients with these lesions typically had more biopsy passes (average 4.9)
  • Acute liver failure (n=12) OR 26.1 for major complication risk
  • Low-molecular weight heparin therapy (n=18)  OR 2.43 for all bleeding risk

Not identified as risk factors for complications in this cohort:

  • Low platelet count (<70 [n=14])or coagulopathy (INR>1.7 [n=18]),  –all received blood products before biopsy
  • Aspirin treatment (often used in transplant population to prevent hepatic artery thrombosis) (n=55)  OR 0.96
  • Liver transplant patients (n=97) -odds ratio was lower than entire cohort (OR 0.52)

Additional references:

  • -JPGN 2011; 53: 202. Good safety results with IR liver biopsy, n=249. 2/249 had drop in Hgb of 2g -no transfusions needed, no mortalities.
  • -Clin Gastro & Hep 2010; 8: 877. 0.5% complication rate, n=2740. No deaths. Bleeding was most common risk –increased with advanced liver disease.
  • -Hepatology 2009; 49: 1017. AASLD Position Paper
  • -Gastroenterol 1978; 74: 101 & 103. Early article discussing safety of LBx and that most pts could be d/c’d w/in 6 hours.
  • -JPGN 2005; 41: 639. Safety of liver biopsy in infants less than 3 months (w/o U/S). complication rate was 18% including sedation-related, 1 bile leak, and 3 needed PRBCs.
  • -JPGN 2003; 36: 364. Ultrasound useful.
  • -Can J Gastroenterol 2000; 14: 543-548.  Mortality rate 3/10,000
  • -Clin Perspectives Gastroenterol 2002; 5: 117. Rec ultrasound, plts >75K, PT c/in 3 secs of normal; observation for 3-6hrs in adults.
  • -NEJM 2001; 344: 495. Liver bx review.
  • -Hepatol 27: 1220-26, 1998. U/S marking reduces complications
  • -Fox VL, Cohen MB, Whitington PF, Colletti RB. Outpatient liver biopsy in children (n=450). J Pediatr Gastroenterol Nutr 1996;23:213-6.  High mortality rate reported, primarily in bone marrow transplant patients
  • -JPGN 2000; 31: 536-39. Safety of liver biopsy in children, n=249.

α1-antitrypsin review

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For a brief and useful review of α1-antitrypsin (A1AT) deficiency: Clin Gastroenterol Hepatol 2012; 10: 575-80.

One of the pieces of information that is fairly new in the review: “the most promising strategy for treating liver disease in patients with A1AT deficiency is to decrease the accumulation of polymerized A1AT by stimulating its autophagy in hepatocytes.”  Both carbamazepine and rapamycin have been capable of this in transgenic mice; this has been associated with reduced liver fibrosis.

General recommendations from review:

  • In patients with cirrhosis due to A1AT deficiency, screening for HCC is appropriate (Looking for trouble)
  • Limit alcohol consumption and tobacco exposure
  • Assure vaccination for hepatitis A & B
  • Decompensated liver disease managed in standard fashion

Additional references:

  • Tegretol may help treat/prevent fibrosis –study in Pittsburgh (at least 14yrs old, ZZ) –can call 855-428-2281 David Perlmutter
  • -NEJM 2010; 363: 1863-64.  Autophagy in A1AT deficiency
  • -Hepatology 2007; 45: 1313. Review of meeting on A1AT deficiency
  • -JPGN 2006; 44: 99. High prevalence of alpha-1 heterozygosity in chronic liver disease. Multiple other polymorphisms may contribute to liver disease in some (heterozygous HFE gene, 1 mutation for Alagille may worsen EHBA [Hepatology 2002; 36: 904-12.], glutathione-S-transferase P1 polymorphism seen c CF liver disease
  • -JPGN 2006; 43: 136-138. Variable degree of liver involvement in Sibs with PiZZ disease.
  • -Clin Gastro & Hep 2005; 3: 390. factors associated c severe dz in adults include male gender and obesity.
  • -JPGN 2003; 37: 347 (62A) NSAIDs may worsen liver dz.
  • -Clin Perspect in Gastro 2002; 5 (1) : 40. (review)

BRIC, PFIC, and nasobiliary drainage

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Case reports, when effective, help clinicians understand meaningful differences in disease presentation; in addition, they highlight practical treatment approaches.  An excellent example of one such case report is the following:

  • Zellos A et al.  JPGN 2012; 55: 88-90

These authors present a case with unique features that highlight some of the clinical problems with benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis (PFIC).  BRIC1 and PFIC1 are associated with mutations in ATP8B1; BRIC2 and PFIC2 are associated with mutations in ABCB11.  The primary difference between BRIC and PFIC is the phenotypic expression.  In BRIC, individuals have episodes of cholestasis; in PFIC, progressive chronic liver disease develops in the first months of life.  PFIC2/ABCB11 mutations cause defective bile salt export pump (BSEP) at the bile-canniculus membrane.

Both ATP8B1 and ABCB11 intrahepatic cholestasis conditions present in a similar fashion with low GGT values.  In this case report, a 5-year-old presented with jaundice, acholic stools and dark urine.  His laboratory values revealed an ALT of 60 U/L, direct bilirubin of 7.6 mg/dL and gamma-glutamyl transpeptidase (GGT) of 10 U/L.  Initially, after exclusion of other liver conditions (eg. NL MRCP, copper studies, α-1 antitrypsin, autoimmune serology, infectious etiologies), the authors suspected ‘a clinicopathologic intergrade between BRIC and PFIC’ likely due to ATP8B1 as there was BSEP expression on liver biopsy immunostaining.  After sequencing did not demonstrate any ATP8B1 mutations, the authors identified two heterozygote mutations in ABCB11.

From a treatment standpoint, once nasobiliary drainage (NBD) was in place, the patient quickly improved.  This occurred after >6 weeks of failure with urosdeoxycholic acid/conservative measures.  As a precaution, the authors cultured the bile once a week and instituted antibiotic treatment when positive cultures were identified.

One other point alluded to by the authors is that the natural history of BRIC2 is poorly described.  Whether this disorder is truly ‘benign’ as the name suggests is unclear.  In patients with similar mutations who develop PFIC2, there is a high risk of hepatocellular carcinoma (HCC).

Intrahepatic Cholestasis Genes/Disorder (Clin Liver Dis 2006; 10: 27-53.)

Gene: Disorder (protein)
ABCB11: PFIC 2, BRIC 2 (BSEP)
ABCB4: PFIC 3, ICP (MDR3)
CFTR: CF (CFTR)
ATP8B1: PFIC1 -Byler’s (FIC1), BRIC, GFC -Greenland Familial
CLDN1: NISCH (Claudin 1) -neonatal sclerosing cholangitis/icthyosis
VPS33B: ARC syndrome (Vascular protein sorting 33) -arthrogryposis-renal dysfn-cholestasis, low GGT
AKR1D1: BAS: Bile acid synthetic defect: neonatal cholestasis with giant cell hepatitis
(5β-reductase)
HSD3B7: BAS (C27-3β-HSD)
CYP7BI: BAS (CYP7BI)
TJP2: (ZO-2) FHC: Familial hypercholanemia (tight junction protein)
BAAT: FHC (BAAT)
EPHX1: FHC (epoxide hydrolase)
JAG1: Alagille (JAG1) JAG1 is transmembrane cell-surface protein important in regulating cell fate during embryogenesis
PKHD1: ARPKD (fibrocystin -important in ciliary function and tubulogenesis)
PRKCSH: ADPLD (hepatocystin)
ABCC2: Dubin-Johnson syndrome (MRP2)
CIRH1A: NAIC -N Amer Indian childhood cirrhosis (Cirhin)

Additional references for BRIC/low GGT PFIC:

  • -JPGN 2010; 51: 494.  Use of biliary diversion –helpful in 18 PFIC2 cases with long-term f/u.
  • -Liver Transplantation 2010; 16: 856.  6 patients developed recurrent low gamma-glutamyl transpeptidase cholestasis, that mimics BSEP disease, following transplantation. All had documented genetic defects in ABCB11 that were predicted to lead to a congenital absence of BSEP protein.
  • -NEJM 2009; 361: 1359. Recurrence of BSEP deficiency p OLT due to antibodies against BSEP
  • -Hepatology 2010; 51: 1645. n=62 children & clinical course.
  • -Gastroenterol 2008; 134: 1203. Severe BSEP –82 different mutations in 109 families. (n=132 patients)
  • -JPGN 2008; 46: 241. Excellent review. FIC1 caused by mutations in ATP8B1, PFIC 2 caused by mutations in ABCB11 which encodes BSEP – bile salt export pump. Increased risk of HCC in PFIC2 especially.
  • -J Pediatr 2007; 150: 556.  Increase risk of HCC in PFIC2.
  • -Hepatology 2006; 44: 478-486. Cases of pediatric HCC in PFIC-2
  • -Gastroenterol 2006; 130: 908. Review of canalicular transport defects.
  • -Hepatology 2005; 42: 222. summary of cholestasis workshop
  • -Gastroenterol 2004; 126: 322. Review of bile salt transporters.
  • -JPGN 2002; 34: 7A. FTT, diarrhea persist p biliary diversion or transplant.

PFIC3 -High GGT

  • -Gastroenterol 2003; 124: 1037-42. MDR3 mutations causing cholelithiasis, cholestasis, biliary cirrhosis, & pregnancy cholestasis.
  • -Gastroenterol 2001; 120: 1448-1458. n=31 cases. MDR3 mutations. ABCB4 gene
  • -Gastroenterol 2001; 120: 1459-67. Gallbladder stones & chronic cholestasis in 6 MDR3+ pts. Avg age of presentation: 2.9yrs. Avg age of Tx: 7.5yrs.  Sx/S : high ggt cholestasis, pruritus, intrahepatic cholestasis of pregnancy in heterozygotes (& c contraception)
  • -Hepatology 1996; 23: 904-8. MDR3 gene assoc c PFIC

Advice on drug-induced liver injury (DILI)

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Practical information and advice on continuing or stopping drugs with associated hepatoxicity is available from a recent commentary (Gastroenterol Hepatol 2012; 8: 333-36).

Most drugs with a “bump” in aminotransferases do not need to be stopped.  Many drugs induce an “adaptive response” in which elevated LFTs will spontaneously resolve; this is most common in the first 12 weeks of drug usage.  This type of response must be distinguished from an immune reaction/hypersensitivity response which is much more likely to progress.  A hypersensitivity response could include rash, fever, and eosinophilia.

Recommended STOP RULES:

  • Drugs that cause symptomatic hepatitis: abdominal pain, jaundice, loss of appetite.
  • ALT values that exceed 8 times the ULN
  • ALT values >3 times the ULN and Bilirubin >2 times the ULN

Other caveats:

  • If the ALT value is >3 times the ULN but not associated with symptoms or rise in bilirubin, the drug can likely be continued with periodic monitoring.
  • ALT values >5 times the ULN require more intensive monitoring.
  • Hy’s law (named for Hyman Zimmerman): AST or ALT > 3 ULN AND   bili > 3 ULN indicate serious hepatotoxicity with >10% mortality rate.
  • Statins have similar rates of hepatotoxicity as the general population
  • Acetaminophen accounts for 40-50% of the 2000-2500 U.S. cases per year of acute liver failure (ALF).  Of the remaining cases of ALF, about 12% (250-300) are due to other cases of DILI.  Isoniazid is the 2nd most common cause of ALF due to DILI with about 50 cases.
  • Potential risk factors for DILI include alcohol usage, obesity, adult age group, and female gender.

Additional blog entries and references:

When death is on the line

Pediatric pharmaceutical poisoning

  • -J Pediatr 2011; 158: 802. Developing liver toxicity with valproic acid (VPA) is a contraindication to OLTx (even in the absence of documented mitochondrial dz). Rx with carnitine and d/c VPA. 82% of 17 children died w/in 1 yr of OLTx. POLG1 mutations are associated with Alpers syndrome. (Ann Neurol 2004; 55: 706.)
  • -NEJM 2009; 360: 1575. propylthiouracil assoc c liver failure in ~1 in 2000
  • -JPGN 2008; 47: 395-405. Drug-related hepatotoxicity and acute liver failure.
  • -NEJM 2003; 349: 474. (review)
  • PDF] What Do We Mean by Looking?  FDA powerpoint with related information

Pediatric NAFLD Position Paper

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A previous blog post (NAFLD Guidelines 2012) described comprehensive, up-to-date NAFLD guidelines from AASLD, AGA, and ACG.   Another group of experts from ESPGHAN (European Society for Pediatric Gastroenterology, Hepatology, and Nutrition) has also published a position paper on the diagnosis of NAFLD in children; coincidentally, these were published recently as well (JPGN 2012; 54: 700-13).

While there is some overlap in the information between the two guidelines, there are some notable differences.  The JPGN manuscript does include a nice differential diagnosis list  which can cause fatty liver disease (Table 2), including some rare entities like Dorfman-Chanarin syndrome, Cantu syndrome, Madelung lipomatosis, and numerous medications.  This review has more emphasis on etiology.

Table 3 lists a recommended workup in children with suspected NAFLD:

  • Standard liver function tests/blood counts/coagulation studies
  • Fasting glucose & insulin
  • Lipid profile
  • Glucose tolerance test & glycosylated hemoglobin
  • Calculation of HOMA-IR, markers of insulin resistance

AND Tests to exclude other liver diseases: 

  • Lactate, uric acid, iron, ferritin, pyruvate
  • Copper, ceruloplasmin, 24-hour urinary copper
  • Sweat test
  • Celiac serology (TTG IgA and serum IgA)
  • α-1-antitrypsin levels and phenotype when indicated
  • Amino and organic acids
  • Plasma free fatty acids and acyl carnitine profile
  • Urinary steroid metabolites
  • Other specific tests as suggested by evaluation (eg. viral hepatitis panel, serum immunoglobulins, liver autoantibodies)

When one looks at the recommended diagnostic algorithm (Figure 1) and tests outlined, these guidelines are not nearly as practical as the NAFLD guidelines from AASLD, AGA, and ACG and often contradictory between the tables/figures and the text.  How much would it cost for the recommended testing if/when extrapolated to the vast numbers of individuals with these disorders?  In addition, a much more limited diagnostic approach is suggested in the final section than outlined in Table 3 and Figure 1.

Imaging: these authors advocate LFTs and ultrasonography in all obese children (> 3 years) and adolescents.  If normal LFTS and sonography, the algorithm suggests the use of MRI if clinical signs of insulin resistance.  Later, the authors conclude “MRI is not cost-effective.”

Liver Biopsy: while the authors state that there is “no present consensus or evidence base to formulate guidelines” for liver biopsy, this is not well-reflected in their diagnostic algorithm in which arrows point to liver biopsy in almost everyone –either early liver biopsy or eventual biopsy in patients with persistent disease.  Accepted liver biopsy indications, according to the executive summary, include the following:

  • Exclude other treatable disease
  • Suspected advanced disease
  • Before pharmaceutical/surgical treatment
  • Research purposes

My conclusion about this position paper is it is less helpful than the AASLD/AGA/ACG guidelines.  In fact, when extensive diagnostic testing is recommended by experts, it is fortunate that other expert guidelines are available that support a more cost-effective approach.  In NAFLD cases that seem atypical and especially in the very young patient, this reference may still be helpful.

Geographic Inequity for Liver Transplantation

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Organ scarcity remains a big problem for liver transplantation.  Use of the Model for End-Stage Liver Disease (MELD) score was intended to address inequity in liver transplantation allocation.  However, it has not been successful.  One recent study which examines donation after cardiac death versus brain death (Liver Transpl 2012; 18: 630-40) also yields some insight into liver transplantation allocation across the U.S.

In Figure 3, the thirty-day probability of receiving a liver transplantation (brain death donation) for patients with MELD score >20 was compared across UNOS regions.  In regions 3 and 11 (Southeastern U.S. extending to Kentucky and Virginia), the rate was ≥40%.  In region 1 (Northeastern U.S) and region 5 (Southewestern U.S.) , the rates were 9.6% and 11.8% respectively.  Thus, some patients with the exact same MELD score have a 4-fold higher probability of receiving a liver transplant.

Related blogs:

Alive and well? 10 years after liver transplantation

Picking winners and losers with liver transplantation allocation

Big gift, how much risk

Sarcopenia, fatigue, and nutrition in chronic liver disease

Case finding for hepatitis C

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A previous post noted the failure of risk-based screening for hepatitis C virus (HCV) (Unknown unknowns for Hepatitis C).  Because risk-based screening has not been effective, the CDC has proposed a different strategy, one time testing of all baby boomers:

http://www.cdc.gov/nchhstp/newsroom/HepTestingRecsPressRelease2012.html

“On the eve of the first ever National Hepatitis Testing Day (May 19), the Centers for Disease Control and Prevention is issuing draft guidelines proposing that all U.S. baby boomers get a one-time test for the hepatitis C virus. One in 30 baby boomers – the generation born from 1945 through 1965 – has been infected with hepatitis C, and most don’t know it.”

NAFLD Guidelines 2012

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Given the pervasiveness of Non-alcoholic Fatty Liver Disease (NAFLD), updated practice guidelines are worth a look (Hepatology 2012; 55: 2005-23, also in Gastroenterology 2012; 142: 1592-1609)).  While the review includes updated information on incidence, prevalence, risk groups, natural history, the focus remains on specific graded recommendations.

These AGA/AASLD/ACG guidelines do not recommend screening adults due to uncertainties surrounding diagnostic tests and treatment.  This includes high risk populations such as diabetics and bariatric patients.  In addition, unlike recent obesity guidelines from the AAP (Pediatrics 2007; 120: S164-192), these guidelines do not recommend screening children for NAFLD.

Specific management recommendations:

  • Exclude competing etiologies in patients with suspected NAFLD: iron studies, autoantibodies, Wilson’s, viral hepatitis, celiac serology, muscle disease
  • Consider liver biopsy in higher risk patients: metabolic syndrome patients, patients with higher NAFLD Fibrosis score, or before treatment
  • Serum/plasma CK18 is promising biomarker.  Not recommended for routine practice at this time.

Treatment Recommendations:

  • Weight loss (3-5%) helps steatosis and greater losses (up to 10%) may be needed to improve necroinflammation.
  • Metformin –not recommended for liver disease in NASH/NAFLD.
  • Pioglitazone can be used to treat steatohepatitis; however, “long-term safety and efficacy of pioglitazone in patients with NASH is not established.”
  • Vitamin E at 800 units/day improves liver histology in biopsy-proven NASH.  Not recommended without biopsy-confirmed NASH, in diabetic patients, or patients with cirrhosis.  Concern with Vitamin E in adults has been an association with increased all-cause mortality in some studies (but not in others).
  • Avoid alcohol in patients with NAFLD

Website to download PDF version:

http://www.gastro.org/journals-publications/news/societies-develop-new-nafld-clinical-practice-guideline

Another opinion on which patients to biopsy:

http://www.gastro.org/journals-publications/aga-perspectives/june-july-2012/should-we-routinely-do-liver-biopsy-in-nafld-patients

Related posts:

A liver disease tsunami