Liver Shorts -June 2020

SH Ibrahim et al. Hepatology 2020; 71: 1474-85.  Thorough review of liver diseases in the perinatal period and relationship of the maternal-infant interactions.  Liver diseases discussed include GALD which has “strikingly normal or near normal transaminases” despite liver failure (most common etiology).  Treatment for GALD includes IVIG (1 g/kg) along with subsequent double-volume exchange transfusion.  The review covers maternally-transmitted viral infections, fatty liver disease, and acute fatty liver disease of pregnancy (AFLP); AFLP is most commonly caused by LCHAD but can be caused by other defects in fatty acid oxidation.

RT Khalaf, RJ Sokol. Hepatology 2020; 71: 1486-98. This review focuses on intestinal failure-associated liver disease (IFALD).  The review provides an in-depth discussion of intravenous lipid emulsions and other factors implicated in the pathogenesis.

  • Risk factors: bacterial overgrowth, central line infections, recurrent sepsis, prematurity, parenteral nutrition composition, and micronutrient imbalances
  • Protective factors: early enteral nutrition, cycled parenteral nutrition, glucagon-like peptide 2, preservation of ileocecal valve, small bowel lengthening when appropriate
  • While the authors acknowledge that lipid minimization often improves cholestasis, they advise caution due to concern for both essential fatty acid deficiency and detrimental effects on brain growth.
  • Prevention of central line infections with use of ethanol locks is important and effectively reduces the rate by more than 80% (though currently costs of ethanol locks have skyrocketed: FDA Safety Initiative Complicit in Ethanol Costing $30,000 for 1 oz)
  • The authors note that long-term survival from intestinal transplantation is only 40% at 10 years indicating benefit of ongoing parenteral nutrition management if feasible.

Related blog posts:

PL Valentino et al. JPGN 2020; 70: 547-54. This article discusses potential management of Wilson disease diagnosed in infancy based on ATP7B genetic testing. Very little evidence presented.  Suggests starting Zinc therapy at an early age and monitoring for copper deficiency along with efficacy.  More precise recommendations regarding urine copper goals for children would be helpful as well.

Large (n=112, median age 38 years) prospective observational study of Acute Hepatic Porphyria. L Gouya et al. Hepatology 2020; 71: 1546-58. Key findings from EXPLORE group:

  • Chronic symptoms were noted in 65%; 46% had daily symptoms. Symptoms including body pains, trouble sleeping/tiredness, anxiety, GI symptoms (eg. nausea) and weakness.
  • During the 2-year study period, 88% experienced a total of 483 attacks; 77% of these attacks required treatment at a health care facility or hemin administration
  • Median annualized attack rate was 2.0
  • UrineDelta-aminolevulinic acid (ALA) and porphobilinogen (PBG) compared with upper limit of normal at baseline and increased further during attacks.
  • At baseline, 16% had elevations of liver aminotransferases
  • Related reference: M Balwani et al. Hepatology 2017; 66: 1314-22. Acute Hepatic Porphyrias -Review. Current recommendations include gene sequencing to confirm all biochemical cases. Biochemical tests are spot urine testing of porphobilinogen (PBG), 5-aminolevulinic acid (ALA), and porphyrins. A normal urine PBG in symptomatic patients “excludes the three most common acute hepatic porphyrias.”  For those with abnormal studies, this reference is a handy.

Automated ascites pump. F Wong et al. Liver Transplantation 2020; 26: 651-61. In this study with 30 patients, interventional radiology placement of an “alfapump” helped manage refractory ascites in cirrhosis.

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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

Brief Updates: COVID-19/Hydroxychloroquine, GALD, Anorexia Nervosa, and Esophaeal-gastric Dissociation Outcomes

Recent reports indicate that hydroxychloroquine is not likely effective for COVID-19.  Submitted manuscript: Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19 Commentary from Politco: More deaths, no benefit from malaria drug in VA virus study

An excerpt: A malaria drug widely touted by President Donald Trump for treating the new coronavirus showed no benefit in a large analysis of its use in U.S. veterans hospitals….The study was posted on an online site for researchers and has been submitted to the New England Journal of Medicine, but has not been reviewed by other scientists….About 28% who were given hydroxychloroquine plus usual care died, versus 11% of those getting routine care alone. About 22% of those getting the drug plus azithromycin died too, but the difference between that group and usual care was not considered large enough to rule out other factors that could have affected survival…The NIH and others have more rigorous tests underway.

HS Fischer et al. JPGN 2020; 70: 444-9. This study examined outcomes of 12 patients with gestational alloimmune liver disease over an 11 year period. Key findings:

  • Median age at diagnosis of neonatal acute liver failure (NALF): 2 days
  • All 12 received exchange transfusion ET).  Common signs: hypoglycemia, hyperferritinemia, cholestasis, and coagulopathy. Direct bilirubin typically increased after ET.
  • Outcomes: survival without transplantation occurred in 10 of 12.  Two patients died including one after liver transplantation.
  • “Most cases of NALF are due to GALD and should be timely treated with ET and IVIG.”  Current testing is lacking with regard to sensitivity and specificity, “early ET [and IVIG] before reaching a definitive diagnosis was associated with favorable outcomes.”

Related blog posts:

JE Mitchell, CB Peterson. Anorexia Nervosa (good review). NEJM 2020; 382: 1343-51.

Key points: 

  • Anorexia nervosa is a severe psychiatric disorder
  • Indications for hospitalization include profound hypotension or dehydration, severe electrolyte abnormalities, arrhythmias or severe bradycardia, suicide risk or BMI ≤15

Related blog posts:

S Battaglia et al. JPGN 2020; 70: 457-61. This retrospective study examined outcomes in 30 patients with severe neurologic impairment who underwent esophageal-gastric dissociation (E-GD) between 2000-18 and had a median follow-up of 3.5 years. E-GD was completed at a median age of 6.5 years. “Primary” E-GD was done in 23 and “Rescue” (after fundoplication) was done in 7 patients.

  • Hospitalizations and episodes of chest infections significantly decreased; weight improved
  • Vomiting and reflux resolved in all patients
  • 6 (20%) experienced early complications including 3 who needed surgery (1 obstruction, 1 volvulus, and 1 pyloric obstruction); 3 (10%) had late complications (adhesions/obstruction in 1, incisional hernia in 1, large para-esophageal hernia in 1)
  • There were no surgery-related deaths

The authors, in their discussion, compare primary E-GD with fundoplication.  Many of the referenced studies indicate that E-GD may have improved outcomes in the population of children with severe neurologic impairment, but also with a higher frequency of complications.  They conclude that E-GD “is a valid alternative to fundoplication…but is is just as effective and feasible when undertaken as a ‘Rescue’ procedure following failed surgical antireflux treatment.”

My take: The frequency of fundoplication operations have dropped markedly with increasing use of gastrojejunal tube placement.  In my view, I would usually recommend E-GD for ‘rescue’ after fundoplication failure.

A recent yard sign from my wife for neighborhood walkers during the pandemic


Neonatal Cholestasis for Neonatologists

I recently had the opportunity to review the topic of neonatal cholestasis with my neonatal colleagues.  I reviewed two related conditions: parenteral nutrition associated liver disease (PNALD) and neonatal acute liver failure (NALF).  Some of the material incorporates recommendations from NASPGHAN cholestasis guidelines and from NASPGHAN cholestasis slidesets. Much of the slideset information is publicly available on a YouTube lecture by Dr. Linda Book (link at bottom).

Full lecture: Neonatal Cholestasis for Neonatologists

Some screenshots:

Related blog posts:

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.


Changing Approach to Neonatal Acute Liver Failure

A recent review (SA Taylor, PF Whittington. Liver Transplantation 2016; 22: 677-85) provides several important concepts for practitioners who may need to manage neonatal acute liver failure.

The most common etiologies (in parenthesis the approximate percentage of cases in their experience):

  • Gestational alloimmune liver disease (GALD) (60-90%)
  • Viral hepatitis (20-30%)-particularly HSV, followed by HHV-6, and rarely CMV
  • Hemophagocytic lymphohistiocytosis (HLH) (<10%)
  • Mitochondrial hepatopathy (<5%)
  • Rare causes include galactosemia, hereditary tyrosinemia type 1, and hereditary fructose intolerance. (<1%)  In addition, bile acid synthetic defect 5-beta-reductase deficiency can cause neonatal liver failure.

While INR ≥2.0 was used in the PALF studies as a primary defining feature of liver failure, since an INR of 2.0 can occur in the normal newborn, the authors recommend using an INR≥ 3.0 for neonatal liver failure.

Their Table 1 helps provide some important differences, Distinguishing features:

  • With GALD, ALT values are typically <100 due to underdeveloped hepatic parenchyma and ferritin is typically >800 and <7000.  IUGR is frequent (70-90%) as is hypoglycemia. Hepatosplenomegaly is uncommon.
  • With viral infections and HLH, ALT values are typically high, ferritin often very high, hepatosplenomegaly is common. IUGR is rare.
  • With mitochondrial disorders, ALT typically is between 100-500, ferritin levels are variable, and IUGR occurs in 20-30%.  A distinguishing feature is lactate: pyruvate ratio and ketone body ratios.
  • By thinking carefully about the reasons for liver failure in the neonatal period and not trying to examine for every possible liver disease, the use of these variables can expedite the evaluation and decrease the cost.  Genetic testing is not recommended due to the slow turnaround time, “and many diseases that are prominent causes of cholestatic disease …just do not cause NALF.”

With regard to treatment, the authors advocate use of IVIG if suspicion for GALD.  If workup (lip biopsy and/or MRI) confirms GALD then exchange transfusion and repeat IVIG is recommended.

My take: This reference should be helpful when managing a neonate with severe liver disease.

Related blog posts:

Set from the Musical "Beautiful"

Set from the Musical “Beautiful”

A new GALD phenotype

A previous post discusses gestational alloimmune liver disease (GALD) (The more you know the more you see) and provides a number of references.  Additional insight into GALD comes from a recent case report (Pediatrics 2012; 129: e1076-79).

In this report, ascites is recognized in utero at 29 weeks.  This ascites was determined to be due to compression of the vena cava by hypertrophy of the hepatic caudate lobe.  When the patient was delivered at 34 weeks gestation, additional testing revealed normal coagulation parameters, peak ferritin level of 750 ng/ml at day 19, and a nodular liver on ultrasonography.  The patient underwent a liver biopsy via minilaparotomy which confirmed cirrhosis but did not show evidence of iron overload.  Tests for a multitude of other liver diseases were negative.  Liver biopsy stains demonstrated C5b-9 complex in >95% of hepatocytes after treatment with monoclonal antibody.  The detection of a high level of C5b-9 neoantigen is highly specific for  GALD.  Clinically, the patient had spontaneous recovery.

Take home points:

1. While iron overload is a hallmark of GALD, it is likely a consequence and not a cause of this severe liver disease.

2. Identifying atypical GALD cases allows the institution of immunotherapy during future pregnancies which reduces the recurrence risk.

3. The phenotypic spectrum of GALD includes the following:

  • Neonatal liver failure with iron overload
  • Fetal liver failure and/or death with or without iron overload
  • Liver cirrhosis and mild neonatal liver disease without iron overload.  These patients likely require special stains (call Peter Whittington for these patients)

The more you know the more you see

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.