JA Flemming et al. Hepatology 2017; 65: 804-12. This cohort study (2003-2015) of 47,591 adults wait-listed for liver transplantation, using the SRTR registry, showed that the era of direct-acting antivirals for hepatitis C was associated with a drop of 32% for HCV patients who were listed compared to the numbers listed during the interferon era.
AG Feldman et al. J Pediatr 2017; 182: 217-22. This retrospective study showed that elevated lactate levels (≥2.5 mmol/L) and elevated lactate to pyruvate ratio (≥25) were NOT predictive of mitochondrial diseases in pediatric patients who presented with acute liver failure.
AG Feldman et al. J Pediatr 2017; 182: 232-38. This retrospective cohort study showed a high rate of vaccine preventable illnesses (VPIs) following liver transplantation (n=2554), occurring in 1 of 6 liver transplant recipients. Most common infections was RSV; most common VPIs: rotavirus and influenza
Saint Chappelle, Paris
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.
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From Jeff Schwimmer’s twitter feed:
A story in the Boston Globe highlighting the difficulty of differentiating Mitochondrial Disease from Medical Child Abuse; the latter term is now preferred over Munchausen Syndrome by Proxy. Her gastroenterologist was involved due to stooling problems (this child underwent a cecostomy tube) and feeding issues:
b.globe.com/1b6Vy4E -part 1.
PART 2: The family battles the state.
More bad press or Boston Children’s:
A recent review provides advice for the evaluation of the child with suspected mitochondrial liver disease (JPGN 2013; 57: 269-79).
- Acute in a child with no history of hepatic dysfunction
- Chronic liver and CNS dysfunction
- Onset of liver disease in patient with known CNS disorder
Suggested Tiered Diagnostic Evaluation: Table 1 provides extensive suggestions.
- 1st tier: CMP, INR, AFP, CPK, Phos, CBC/d, ammonia, Lactate/pyruvate (preferably 1 hour after feeding), serum ketone bodies, serum acylcarnitine profile, carnitine profile, urine organic acids, serum amino acids, urine acylglycines and 2-ethylmalonic acid quantification, plasma thymidine (especially if intestinal dysmotility), quantitative serum methylmalonic acid, CSF analysis (lactate and pyruvate, amino acids, protein)
- 2nd tier: genotyping for more common genes (eg. panel with POLG1, DGUOK, MPV17), other genetic tests based on tier 1 testing (see table for details)
- 3rd tier: liver biopsy, skin biopsy, and muscle biopsy (see table for details)
- 4th tier: additional genetic tests based on 1st three tiers
Table 2 describes potential evaluations in other organs. For example, for brain, MRI, EEG and CSF.
Table 3 lists ~27 mutation/syndromes and clinical features.
The last three words from the conclusion of the publication are not supported by the review. The authors state that this systematic approach “can aid in making a timely, accurate, and cost-effective diagnosis.” While the authors do not provide estimates of the expense of these tests, they are probably very expensive, though less costly than a failed liver transplantation.
Bottomline: “Available technology to aid in diagnosis has improved substantially. Nonetheless, diagnosis of suspected mitochondrial disease in children is complicated.”
Related blog post:
Proven treatments for mitochondrial disorders | gutsandgrowth