Category Archives: Pediatric Gastroenterology Liver Disease

Big gift, how much risk

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When an individual is considering donating a part of their liver, it is no exaggeration to say this may be lifesaving.  In pediatric hepatology, live donor liver transplantation (LDLT) is frequently considered by desperate parents. The risk of this gift has been poorly understood due to a lack of a LDLT registry.

This month (Gastroenterology 2012; 142: 273-80) better data has emerged.  By combining information from UNOS and the Social Security Death Master File, the authors were able to follow 4111 LDLTs (donors) in the U.S. between 1994 and 2011. Key findings:

  • Seven early deaths (1.7 per 1000)
  • Death rate was not affected by portion of liver donated
  • 11 early catastrophic events: early deaths or acute liver failure (2.9 per 1000)
  • Long term mortality was similar to that for live kidney donors and NHANES III healthy participants over 11 year followup (1.2%, 1.2%, and 1.4% respectively)

Although these data are somewhat reassuring, there is a definite increase in mortality and morbidity among LDLT donors.  An editorial in the same issue (pg 207-09) states that LDLT donors are probably healthier than the general population; up to 65% of donor candidates are rejected during the evaluation process.  As such, when survival at 11 years is similar to NHANES III participants, this indicates the likelihood of a detrimental effect on long-term health. Besides early perioperative deaths, suicide and drug overdoses among donors was significant (n=4) and 4% of donors may develop psychiatric problems.  Specific complications include biliary leaks (9%), bacterial infections (12%), and incisional hernias (6%).

At the same time, the direct benefit of this gift including the potential of saving a loved one cannot be measured.  In addition to avoid a protracted uncertain period on the waiting list for a recipient, a donated liver may help another unidentified individual obtain a deceased donated liver.

Additional references:

-Gastroenterology 2008; 135: 468. Donor morbidity/mortality. n=393. 62% without complications. 3 deaths and significant morbidity.
-Liver Transplantation 2006; 12: 499. Review.
-DDW 2003, T Tran, n=56. only 27% of prospective donors c nl histology.
-NEJM 2003; 348: 818-25. (L & R-Lobe) complications from donating in 449. 6% biliary complications, reop in 4.5%, death 0.2%
-NEJM 2002; 346: 1074-1082. & 1038. R lobe Tx.
-J Pediatr 1999; 134: 280.  Results of LDLT: 92% 1 yr survival; higher biliary complications 19-34%.

MicroRNAs and biliary atresia

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The human genome may encode over 1000 microRNAs (miRNAs), which may target about 60% of mammalian genes and are abundant in many human cell types. MicroRNAs are a class of short (18-23 nucleotide) noncoding RNA molecules which act as a negative regulator of target mRNA stability and translation.  This month the interaction of miRNAs with biliary atresia is examined (JPGN 2012; 54: 186-92).

Using a mouse model, the authors identify miRNA-29 overexpression associated with the downregulation of two mRNA targets related to biliary atresia pathogenesis.  The research has several limitations, including the use of adult mice.  The reason why I highlight this study is that miRNAs are helping elucidate basic disease mechanisms and identifying new therapeutic targets.  Some of these same investigators published “Circulating microRNA is a biomarker of pediatric Crohn disease.” (JPGN: 2011;  53(1): 26-33).  In this study, 11 CD-associated serum miRNA were identified with encouraging diagnostic potential.  These specific miRNAs were found in Crohn disease patients but not in controls and patients with celiac disease.  The sensitivity for Crohn disease was over 80%.

Despite this intriguing research, it not clear whether or when miRNAs will have an important role in bedside management.

Additional references:

Help with hepcidin

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Over the past several years, the mechanisms involved in iron overload have been carefully examined and the genetic basis for most of these disorders is now understood.  Several review articles on these disorders have been published; the most recent with excellent diagrams is in last week’s NEJM (NEJM 2012; 366: 348-59 & NEJM 2012; 366: 376-77). Although the process is quite complicated, the most important aspect regarding iron homeostasis is a feedback loop involving hepcidin-ferroportin.  Hepcidin functions as a ‘hypoferremia hormone.’  It down regulates ferroportin release of iron into the circulation.  Hepcidin is also an acute-phase protein and inflammation affects its function.

Hepcidin levels fluctuate in response to the body’s iron needs: more hepcidin causes less iron absorption & less hepcidin causes more iron absorption.

  • Iron balance disorders can usually be attributed to altered hepcidin production.
  • Anemia of chronic disease, though multifactorial, is mostly due to increased hepcidin production in response to inflammation.
  • Hemochromatosis results from genetic mutations causing lack of normal hepcidin production.  The severity of these disorders correlates with hepcidin levels.
  • Hepcidin agonists could be used to treat hemochromatosis and other iron overload conditions (eg. thalassemia with transfusion therapy).  For hemochromatosis, phlebotomy will be less expensive.
  • Hepcidin antagonists could treat anemia of chronic disease

Additional references:

  • -Hepatology 2011; 54: 328.  Review.  Guidelines.
  • -Hepatology 2010; 52: 925.  HFE homozygotes, n=31,192 w low risk of clinical symptoms if ferritin <1000.
  • -Gastroenterology 2010; 139: 393. Review –pathogenesis/dx/Rx
  • -Hepatology 2009; 50: 94.  C282Y/H63D compound heterozygotes (n=180) are at low risk for hemochromatosis-related morbidity compared with control group.
  • -Hepatology 2008; 48: 991.  Review.
  • -Hepatology 2007; 46: 960, 1071.  Review of clinical phenotypes.  Of C282Y homozygotes, only 1-2% develop HCC, 6% cirrhosis, 25% liver fibrosis, 38% Fe overload, 61-75% develop raised serum iron indices.
  • -Hepatology 2007; 46: 1291. Review of hemochromatosis
  • -Hepatology 2007; 45: 253. Review of iron metabolism
  • -NEJM 2004; 350: 2383. Review.  Several genetic mutations associated with clinical phenotype.  type 1: Classic HFE, types 2A & 2B: (Juvenile type)  HJV & HAMP (gene products hemojuvelin & hepcidin), type 3:TFR2 (transferrin receptor 2), and type 4:SLC40A1
  • -NEJM 2005; 352: 1011. Algorithm.  If transferrin saturation <16%, check ferritin.  If ferritin less than 30, Fe-deficiency; if >100, anemia of chronic disease.  If 30-100, check soluble transferrin receptor (level of sTranReceptor/log ferritin less than 1 is c/w anemia of chronic disease whereas when this ratio is greater than 2, c/w combined Fe-def anemia and anemia of chronic disease).  Hepcidin is produced by hepatocytes and regulates iron homeostasis.  Hepcidin interacts with ferroportin, an iron export protein on enterocytes (& other cells), & facilitates internalization and degradation of ferroportin.  It may lead to decreased dietary iron absorption and to retention of iron body stores.  Hepcidin expression can be up-regulated by high iron levels or during acute phase inflammatory responses (thus can contribute to anemia of chronic disease).  Hereditary hemochromatosis associated with low hepcidin levels in the face of increased iron body stores.  Several genes can affect hepcidin loss of function, including HFE, hemojuvelin (HJV), and transferrin receptor 2 (TFR2).
  • -Gastroenterology 1996; 110: 1107.  Sentinel article discussing long-term survival in hemochromatosis and role of iron.

More on ethanol locks

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In a post earlier this week (Four advances for intestinal failure), ethanol locks were discussed.  More on information this subject (Pediatrics 2012: 129: 318-29) comes in a meta-analysis.  These authors identified 4 retrospective studies in pediatric IF populations.  Ethanol locks reduced infections by 81% and line replacements by 72%.  The studies in this meta-analysis overlapped with the six studies cited in the previous post.  Adverse events were rare and included thrombotic events.

Additional reference:

  • -JPEN 2012; 36: 36S-42S

Blood is not enough

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…to resolve the problems of sickle cell anemia.  The effects of transfusions for sickle cell patients’ hepatobiliary function are poorly understood.  By lowering the level of hemoglobin S and reducing sickling, can this lead to improvement in organs damaged by sinusoidal congestion and infarction?  Well probably not (J Pediatr 2012; 160: 281-85).

Strokes are known to occur in 5-10% of sickle cell patients by 20 years of age and if untreated, >50% have recurrence.  This has led to transfusion programs.  The ‘Stroke with Transfusions Changing to Hydrdoxyurea’ (SWiTCH) study is a multi-center randomized trial trying to determine how current treatment (transfusions and chelation) compares with hydroxyurea/phlebotomy for preventing stroke and managing iron overload.  As part of this study, a baseline assessment with ultrasound showed widespread problems -despite an average of 7 years of transfusions.  In this cohort of 149 patients, the following findings were identified:

  • Spleen volumes were increased in more than 1/3rd of patients leading to hypersplenism (low platelet counts). 12 subjects had nonvisible spleens due to autoinfarction.
  • Nephromegaly was present.  This finding is known to occur with sickle cell disease and is a marker of glomerular hyperfiltration.
  • Hepatobiliary disease was nearly ubiquitous.  37 of 148 had previous cholecytectomy; of the remaining, 46 of 111 (41%) had gallstones and 14% had gallbladder sludge.  Liver lengths were significantly longer as well.

Conclusions: Transfusion therapy was insufficient to reverse or prevent organ damage in children with sickle cell anemia.  An important limitation– the severity of the underlying prevalence of organ dysfunction prior to initiation of transfusion therapy was not known.

Additional references:

  • -Blood 2011; 117: 772-9.  Silent cerebral infarcts occur despite regular blood transfusions.
  • -Clin Gastro & Hep 2007; 5: 1469.  Reviews types of sickle cell associated liver disease.
  • -Pediatric Hematology and Oncology.  2006 Mar;23(2): 95-102(8).  Sickle cell intrahepatic cholestasis (SCIC), which is related to intrahepatic sinusoidal RBC sickling (due to relative hypoxia) and can be associated with progressive hepatomegaly, mild transaminitis, extreme hyperbilirubinemia
  • -JPGN 2004; 39: 200.  Review of sickle cell hepatic crisis.  Cholestasis resolves over 3 months.  Acute crisis treated with hyperhydration & transfusion. Cohort of 350; 6 developed hepatic crisis.
  • -J Pediatr 2001; 139: 785-789 & 790-796.  Transfusions and hydroxyurea for SS dz.

The heart connection

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Cardiac changes with biliary atresia (BA) are surprisingly common– Gastoenterology 2011; 141: 1264-72.  In this study, 48 patients with BA, listed for liver transplantation, underwent echocardiography between 2004-2010.  The median age was 8 months.  Significant increases in left ventricle wall thickness (23% increase) and mass (51% increase) were noted; in addition, functional changes were noted as there was an increase in LV shortening fraction (8% increase).  Features of ‘cirrhotic cardiomyopathy’ were evident in 72% of infants (29/40).  The authors conclude that these heart changes likely contribute to prolongation of posttransplant hospitalization.

Additional References:

  • -J Am Coll Cardiol 2010; 56: 539-49
  • -J Hepatol 2010; 53: 179-90.

Hepatic ciliopathies

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As our understanding of pathophysiology improves, frequently this results in reclassification of diseases.  Perhaps the best example in pediatric hepatology is gestational alloimune liver disease/congenital alloimmune hepatitis, formerly called neonatal hemochromatosis  (see previous post).  Hepatic ciliopathies are less commonly discussed and thus far have not resulted in abandoning previous nomenclature. These hepatic ciliopathies are related to fibrocystic disease proteins which localize to the primary cilia.  Ductal plate malformation is the main pathology that underlies the liver disease in ciliopathies.  The characteristics of one of these disorders, congenital hepatic fibrosis (CHF) in autosomal dominant polycystic kidney diseae (PKD) involving 19 patients is described in this month’s JPGN (JPGN 2012: 54: 83-89).  Portal hypertension was the main manifestation.  “Hepatocellular function was preserved and liver enzymes were largely normal.”  In patients with AD-PKD-CHF, this was  due to PKD1 mutations with probable contributions from modifier genes.  One interesting finding was that in the identified families, the parents who were affected by polycystic kidney disease did not have CHF.

Although this study demonstrates that CHF and portal hypertension can occur with AD-PKD, CHF and portal hypertension are a characteristic finding with AR-PKD.  With AD-PKD, the liver cysts originate from biliary microhamartomas (von Meyenburg complexes) and are not in continuity with the biliary tree.  In contrast, patients with AR-PKD have cystic dilatations of the biliary system; this combination is called Caroli syndrome.  Due to these differences, unlike AR-PKD, AD-PKD does not typically result in portal hypertension.

Additional references on congenital hepatic fibrosis:

  • -Hepatology 2010; 52: 2223. Review. Medical/Surgical & Tx options.
  • -Am J Med Genet C Semin Med Genet 2009; 151C: 296-406.  Liver disease and kidney disease in ciliopathies.
  • -NEJM 2008; 359: 1477.  Review of autosomal dominant polycystic kidney disease.  ~80% develop liver cysts.
  • -NEJM 2007; 356: 1560. Nice pic of resected liver with polycystic liver disease in 51 year old.
  • -J Pediatr 2006; 149: 159. Review and NIH protocol for enrolling patients. Clinical GI issues: recurrent cholangitis, portal htn, cholelithiasis, and cholangiocarcinoma.
  • -Pediatr Transplantation 2005; 9: 634-9.
  • -Hepatology 2004; 40: 774-82.
  • -Surg Endosc 2005; 19: 130-32.
  • -Gastorenterol Clin N Am; 2003; 32: 857-75. “Heritable disorders of the bile ducts”


The more you know the more you see

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And the more you see, the more you know.  Case in point: gestational alloimmune liver disease (GALD), also referred to as congenital alloimmune hepatitis (CAH) which itself is often referred to as neonatal hemochromatosis (NH).  Now, GALD is more readily identifiable and has better treatments to prevent progression to liver-related complications.  A recent study (J Pediatr 2011; 159: 612-16) shows that GALD can result in fetal death; this finding is a relatively logical extension from the work in this area over the last decade but would not have been feasible without the prior recognition that most cases of neonatal hemochromatosis stem from GALD.

GALD is mediated by fetal complement via activation of the terminal complement cascade.  The presence of C5b-9 complex, an antigen that is part of this cascade, is unique to cases of NH and allows diagnosis, particularly in case in which extrahepatic siderosis is not present. In the reference above, a retrospective study enabled autopsies of six stillborn fetuses and two extreme premature infants who had family histories compatible with NH (along with appropriate controls); the autopsy cases were identified as having GALD– based on liver immunostains with C5b-9 complex.  The implications of this study for pediatricians:

  • When faced with a newborn with coagulopathy or liver failure with family history of stillbirth, consider linking the events immediately & evaluate for NH.  However, this clue has limited utility as NH is the most frequent reason for liver failure in newborns; though, many  newborns with liver failure are often treated for sepsis prior to consideration of NH.
  • Establishing a proper diagnosis, allows management of subsequent pregnancies.  GALD is extremely likely to recur in subsequent pregnancies & can be treated by administration of IVIG to expectant at-risk mothers.

Additional references:

  • -J Pediatr 2011; 159: 813.  Study of ALF in young infants.  38% were indeterminate, ~14% NH, 12% herpes.  n=148. 60% survived w/o OLT, 24% died, 16% OLT
  • -Hepatology 2010; 51: 2061 (edit 1888). Fetal hepatocyte injury involves terminal complement cascade –very good article from Whittington et al. NH being renamed ‘congenital alloimmune hepatitis’
  • -J Pediatr 2009; 155: 566-71. n=16. 75% with good outcome –Rx’d with IVIG (1gm/kg) and exchange transfusion (7 had double volume ET and 6 had less). Appeared to reduce need for liver transplant. Some response with regard to hypoglycemia was fairly quick but most parameters like coagulopathy improved slowly ~2 weeks. Previous historical survival ~36%. (5 of 10 w transplant and 2 of 9 w/o transplant).
  • -Pediatrics 2008; 121: e1615. Weekly IVIG during pregnancy after 18th week of gestation very effective in preventing severe NH
  • -Hepatology 2006; 43: 654. Review by Whitington. MRI detects disease in ~90%. Mucosal biopsy abnl in about 2/3rds of patients. Explains iron homeostasis and alloimmunity.
  • -Liver Tx 2005; 11: 1323 (ed), 1417. Medical treatment ineffective, try transplant. “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.” –Galen, circa 100AD
  • -JPGN 2005; 40: 544. NH is probably an alloimmune dz.
  • -Lancet 2004; 364: 1690-8.

A liver disease tsunami

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The extent and consequences of nonalcoholic fatty liver disease (NAFLD) are far-reaching and like a tsunami will be quite destructive (Gastroenterology 2011; 141: 1249.)  In this article, the epidemilogy of nonalcoholic steatohepatitis is discussed.  NAFLD was  the 3rd most common cause of liver transplantation in this cohort (n=35781).  It is projected to be the #1 reason for liver transplantation by 2025.  Although the outcomes in NAFLD are similar to other liver transplant patients, it is difficult to imagine that so many patients will need such an aggressive treatment approach.

Another recent article, discusses the correlation of vitamin E, uric acid, and diet composition with histology in NAFLD (JPGN 2012; 54: 90-96).  This study involved 149 patients.  The study demonstrates that in these patients, their diet is insufficient in Vitamin E intake. Also, although reported sugar-sweetened beverage consumption was low, uric acid which often reflects total fructose consumption was associated with NASH histology.  As noted in the references below, concerns about low antioxidants, especially Vitamin E, as well as sugary beverages has been an ongoing concern for NAFLD for at least a decade.

For pediatric gastroenterologists/hepatologists, nonalcoholic fatty liver disease is increasingly common but remains difficult to treat; the best treatment is weight loss.  A recent educational pamphlet was published by the NASPGHAN Foundation (http://www.gastrokids.org/files/documents/digestive%20topics/english/NASPGHAN%20Fatty%20Liver%20Fact%20Sheet%2011.2011%20(1).pdf).  The advice for families is the following:

• Avoid sugar drinks

• Drink mostly water and some low fat milk

• Get at least 60 minutes of physical activity every day

• Limit TV and screen time to one hour or less per day

• Make half your plate vegetables at mealtimes

• Eat breakfast everyday

Other things that can harm the liver should be avoided, like drinking alcoholic beverages.  Studies in teens with NAFLD have shown some benefit from the natural form of Vitamin E.

Although this advice applies to patients with NAFLD, it sounds like good advice for everyone.

Additional References:

  • -Hepatology 2011; 54: 1082.  U/S w ~85% sensitivity in detecting fatty liver.
  • -JPGN 2011; 52: 740.  n=20.  Some improvement in LFTs with culturelle
  • -Gastroenterology 2011; 140: 124.  High prevalence in middle aged US cohort: 46% NAFLD, 12% NASH. n=400.
  • -Hepatology 2010; 52: 472.  High dose ursodeoxycholic acid ineffective for NASH in double blind randomized trial. n=185.
  • -Hepatology 2010; 52: 79.  Meta analysis of trials for NAFLD.  No effective Rx at this point.  Thiazolidinediones helped with steatosis/inflammation but caused wt gain.  L-carnitine helped histology in 1 trial.
  • -Hepatology 2010; 51: 1961, 1972. 1– increased fructose assoc with increased fibrosis in NAFLD. 2–increased HCC risk.  Alcohol intake is addt’l risk factor along with NAFLD.  2.6% of NASH pts with HCC (compared w 4% of similar HCV pts).
  • -NEJM 2010; 362: 1675.  n=247.  Vitamin E 800 IU/day helpful.  Pioglitazone not helpful.
  • -Gastroenterology 2010; 138: 905.  Iron overload, but not HFE mutations, associated with more severe NASH
  • -J Hepatol 2009; 51: 918-24.  Soft drinks assoc with fatty liver independent of metabolic syndrome.
  • -Hepatology 2009; 50: 1818.  Lack of benefit from Betaine.
  • -J Pediatr 2009; 155: 469.  Review.  No evidence-based guidelines for treating in pediatrics –main Rx wt loss/exercise.  Consider obtaining ultrasound evidence.
  • -J Hepatology 2009; 51: 371.  risk factors for fibrosis progression.
  • -Hepatology 2009; 50: 68.  Activity helps NAFLD independent of activity level.
  • -JPGN 2009; 48: 587. review of meds.
  • -Gastroenterology 2008; 135: 1961.  Liver biopsy (in pediatrics) still needed as surrogates not accurate for correlating degree of fibrosis/injury.
  • -Gastroenterology 1999; 116: 1413.  spectrum of pathology in NASH.  Bx correlated with outcome
  • -Gastroenterology 1988; 95: 1056.  Sentinel article on NASH ‘alcohol-like liver disease in non-alcoholics’
  • -Clin Gastro & Hep 2008; 6: 1396.  Bariatric surgery appears to improve or resolve NASH. n=15 studies with 766 paired liver biopsies.
  • -Clin Gastro & Hep 2008; 6: 1249.  Cytokeratin 18 levels associated with NASH in at risk patients (bariatric patients). n=99.
  • -Hepatology 2008; 48: 792-98. NASH increased with age and with presence of DM.  Severe fibrosis assoc with ferritin, ALT, and DM.
  • -Gastroenterology 2008; 135: 1176.  n=74.  Use of pioglitazone for NASH was helpful in adult patients.
  • -Hepatology 2008; 48: 119.  Antioxidants Vit C (500mg)/Vit E (600IU) c lifestyle changes was NOT better than lifestyle changes alone. n=53 children. Rx’d for 24 months
  • -Gastroenterology 2008; 134: 1682.  Review.
  • -Clin Gastro & Hep 2008; 6: 26-29.  Review.  Risk factors for NASH: obesity, age>50y, non-black ethnicity, female, type II DM, HTN, AST>45, AST/ALT ratio >0.8-1, low platelet count.  Rec:  exclude other causes, check U/S or CT, if risk factors, conside liver biopsy, lifestyle modification
  • -Gastro 2007; 133: 1814.   Prevalence data for increased ALT from NHANES 1999-2004.
  • -NASPGHAN 2007 Postgraduate Course Jeff Schwimmer.  20% of NAFLD pts have normal wt.  9.6% of all children have NAFLD.
  • -Clin Gastro & Hep 2007; 5: 496.   n=88; 55% of women with PCOS had NAFLD.
  • -Clin Gastro & Hep 2006; 4: 1537.  Combination of Vit E & urso x 2yrs may be beneficial. n=48.  Regression of steatosis  noted in this small study along with improved enzymes.
  • -JPGN 2006; 43: 413.  Invited review of NAFLD.
  • -NEJM 2006; 355: 2297, 2361.  pioglitazone for NASH -helps with histology; not ready for routine use.
  • -Pediatrics 2006; 118: 1388.  Schwimmer.   n=742 autopsy study; estimates 9.6% overall prevalence of fatty liver for ages 2-19 (>6.5 million in U.S.). 38%  obese had steatosis; 23% of all NAFLD had NASH, 9% had bridging fibrosis
  • -Hepatology 2006; 44: 802, 865.  Long term f/u of NASH (avg 13.6yrs): increased cardiovascular deaths (15.5% vs 7.5% control), increased liver-related deaths 2.8% vs. 0.2% controls.  Risk of HCC and cirrhosis proven.
  • -Hepatology 2006; 44: 458.  Prospective study of 84 children; 7%c >grade I fibrosis; 58% with some fibrosis.  Almost all have evidence of insulin resistance
  • -Clin Gastro & Hep 2006; 4: 639.  Orlistat helped decrease ALT and steatosis on U/S beyond its effect on weight reduction.  n=52.  double-blind, placebo-controlled.  Rx 120mg TID x 6 months.
  • -Liver Transplantation 2006; 12: 523.  Review of NAFLD & Liver transplant.  NAFLD likely the main reason for cryptogenic cirrhosis in adults.
  • -Pediatrics 2006; Schwimmer.   n=954 autopsy study, 32% obese had steatosis; 23% of all NAFLD had NASH, 9% had bridging fibrosis
  • -Aliment Pharm Ther 2005; 21: 871.  pilot study of metformin, 500mg bid in children; 50% nl ALT  (equivocal in adults), high insulin in 95% of pts c NASH
  • -J Pediatr 2003; 143:  500-5.
  • -Hepatology 2005; 42: 641-649. pediatric NAFLD pathology
  • -Hepatology 2004; 40: 1387-95.  Nearly 1 in 3 in US have NAFLD.
  • -Clin Gastro Hepatol 2006; 3: 1260.   Alcohol and NASH are synergistically bad. (increase ALT)
  • -J Pedsiatr 2005; 147: 835.  Low adiponectin in children c NAFLD (lower than other overwt children).
  • -Surgery 2004; 135: 48-58.  Wt loss improves liver histology
  • -Gastroenterology 2005; 128: 1898.  Significant sampling variability (can lead to misdiagnosis)
  • -Hepatology 2005; 42: 44. NAFLD in 25% of pts c clinical liver dz & 20% of pts w/o suspected liver dz (n=3345, Italy)
  • -Clin Gastro & Hepatol 2004; 2: 1048 & 1059 (review/editorial) & 1107. pilot study of VIT E vs VIT E/pioglitazone, n=20.
    NASH in 3% lean, 20% obese, & ~50% morbidly obese.  100% of obese/diabetes have at least mild steatosis, 50% c NASH, & ~20% c cirrhosis.
  • -Hepatology 2004; 39: 770-78.  URSO probably doesn’t help NASH.
    -NEJM 2004; 351: 1147.  n=282 obese children; 11% mod obese c incr ALT, 21% of severely obese.
  • -JPGN 2004; 38: 48.  Rx c vitamin E &/or wt loss.  Both are helpful.
  • -J Peds 2003; 143: 500.  Fasting glucose/insulin, ALT/AST, and BMI are predictive of portal inflammation and fibrosis.  1-4% of all children have elevated transaminases (10-25% of all obese patients).
    HOMA-IR =fasting insulin (microU/ml)/ fasting glucose/22.5.  Insulin resistance is when HOMA-IR is greater than 2.  Fibrosis present in 63% of pts, n=43.
  • -JPGN 2003; 37: 342 (47A) use of metformin 500mg bid, n=10; 3 had transient diarrhea/abd pain. (50A) 3/40 children c NASH c early cirrhosis. 31 c portal fibrosis
  • -Gastroenterology 2003; 125: 1053-59.  Obesity increases risk of death due to cirrhosis.
  • -Clinical Gastro & Hepatology 2003; 1: 384-87.  Use of pioglitazone for NAFLD & obesity.
  • -Gastroenterology 2002; 123: 1702-4, 1705-25. AGA position statement and technical review.
  • -Gastroenterology 2003;124: 71-80.  increased ALT in 2.8% of population -mostly in overwt/obese.
  • -JPGN 2002; 36: 54-61.  With MRI,  21 of 22 (BMI>95th%) c elevated hepatic fat; those c abnl ALT, n=12, had more severe cases of fatty liver c fat content >18%.
  • -Ann Intern Med 1989; 111: 473-8.  Clinical dx of nonalcoholic fatty liver dz without Bx has only 59% predictive value.
  • -Gastroenterology 2004; 126: 1287-92.  Pts c elevated liver enzymes (NASH) are not at higher risk for statin hepatotoxicity.
  • -Gastroenterology 2002; 122: 1649-1657.  Review
  • -NEJM 2002; 346: 1221-1231. Review  AST/ALT ratio greater than 1 suggests increased fibrosis.  Consider bx if obese, greater than 45, type 2 DM, or increased AST/ALT ratio.
  • -Hepatology 2002; 35: 1485-93.  significant complications & decreased survival c obesity-related cryptogenic cirrhosis.  higher rates of progressive HCV & HCC c obesity.
  • -Gastroenterology 2001; 121: 710-724.  Review.
    Reasons for Liver Bx  1. poor correlation between clinical/lab findings & histology –thus for staging  2. assure correct dx; may be wrong in ~44%
  • -Clin Gastro & Hepatology 2004; 2: 262.  Coexistant DM worsens outcome in NASH.
  • -J Pediatr 2000; 136: 727. N=2450.  6% of overweight children with increased ALT, 10% of obese children.  1% of obese children with 2x normal.  50% of obese adolescents with alcohol ingestion (4 or more/month) had increased ALT.  Decreased antioxidants, elevated triglycerides, increased age, and increased hgbA1C were addt’l risk factors.
  • -Gastroenterology 2001; 121: 91-100.  HTN, insulin resistance, and ALT were predictors of fibrosis.
  • -J Pediatr 2000; 136: 734. N=11. Daily vitamin E 400-1200 IU/day noramalized ALT in patients c NASH.
  • -J Peddiatr 2000; 136: 739.  Ursodeoxycholic acid is not effective in NASH. N=31.
  • -J Pediatr 1999; 134: 132 & 160..  Low antioxidants with NASH

Minimizing malnutrition in Biliary Atresia

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A retrospective study in Liver Transplantation reviews a single center experience with the use of parenteral nutrition (PN) in patients with end-stage liver disease due to biliary atresia (Liver Transpl 2012; 18: 121-129).  In this study which spanned the past twenty years, 25 PN BA patients were compared to 22 non-PN BA patients –all patients were younger than 36 months.  PN was started when maximal enteral nutrition failed to improve markers of malnutrition (triceps skinfold thickness, & mid-arm circumference).  Among the PN BA patients, there was a higher gastrointestinal bleeding rate and ascites; however, there was no difference in the rates of bacteremia, length of intensive care unit stay after liver transplantation, or patient/graft survival.  The authors speculate that the outcome for the PN BA patients would have been much worse without the PN as malnourished BA patients are at increased risk for graft failure and post-transplant complications.  It is noteworthy that PN patients did have progression of their liver disease that seemed to accelerate with the administration of PN, perhaps due to PN-associated cholestasis.  Specific changes included higher bilirubin levels, lower platelet counts, worsened coagulopathy, and higher calculated PELD scores.

Additional References:

  • Hepatology 2007; 46: 1632-38.  Growth failure and outcomes in infants with BA.
  • J Pediatr 2005; 147: 180-85.  Outcomes of 755 BA patients listed for liver transplantation.