There are over 130 different types of CDG with 41 that have liver involvement; 7 with a hepatopathy and 34 with in the context of multisystem disease.
Transferrin isoform analysis (Isoelectric focusing or high-performance liquid chromotography) detects about 50% of the CDGs; hence, genetic panel or exome sequencing is needed for diagnosis in many cases.
4 cases of MMF hepatoxicity are presented along with EM changes which revealed unequivocal mitochondrial abnormalities similar to those seen in primary and secondary mitochondrial disorders
MMF hepatotoxicity was confirmed in mouse study showing that MMF caused various stress changes in the mitochondria
Conclusion: Although MMF is safe for the majority of patients, MMF can cause mitochondrial stress, which may trigger more severe mitochondrial abnormalities in a small subset which can be evident with EM.
This study examined the clinical data from 182 pediatric patients. WD was diagnosed at a mean age of 10.7 years. Overall survival at 20 years of followup was 98% and patient and transplant-free survival was 84% at 20 years.
In this retrospective study with 31 children with Wilson’s disease (most of whom had had previous penicillamine), those who received more than 20 mg/kg/day of trientine therapy had increased adverse effects compared to those who received less than 20 mg/kg/day: 63% vs 7%; median followup was 60 months. In addition, there was not increased response to higher doses. The authors note that trientine had lower incidence of adverse effects compared to penicillamine and “appears to be the preferred” as a first-line treatment.
In this prospective cohort with 350 participants (all with either PiZZ (90%) or PiSZ (10%) and native livers), 278 (79%) entered the cohort (in 2007 or later) without portal hypertension and 18 developed portal hypertension during follow-up. Portal hypertension was defined by development of ascites, varices or combination of splenomegaly/thrombocytopenia. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. Median length of followup was 2.5 years. My take: While most children with Alpha-1-Antitrypsin Deficiency do well, monitoring is warranted as some will develop progressive liver disease (even in the absence of neonatal cholestasis).
In this phase 2 double-blind study with 78 patients with NASH, at week 24, the aldafermin group had a significant reduction in absolute liver fat content (reduction of 7.7%) compared with placebo (reduction of 2.7%) (P=.002). Fibrosis improvement (1 stage) with no worsening of NASH was achieved in 38% of patients receiving aldafermin vs 18% of patients receiving placebo (P = .10). And, NASH resolution with no worsening of fibrosis was observed in 24% of patients given aldafermin vs 9% of patients given placebo (P = .20)
J Ge et al. Hepatology 2018; 68: 1101-10. This study reviewed liver donation offers between 2010 to 2014. This study found that 5.6% of men (293/5202) and 6.2% of women (179/2899) received a pediatric donor as a first offer. Women, but not men, who received a pediatric first offer had a lower risk of waitlist mortality than with those who received adult organ offers. The authors recommend that “offers of pediatric donor liver be prioritized to women, who are generally shorter stature, once alllocation to the entire…pediatric waitlist pool has occurred.”
CA Chapin et al. Hepatology 2018; 68: 1087-1100. This study found that patients with indeterminate pediatric acute liver failure (iPALF) have a unique pattern of dense CD8+ T-cell infiltrate that is also perforin-positive adn CD103-positive. These CD8+ cells are a biomarker for immune dysregulation. These CD8+ dense pattern was found in the 27 of 33 patients with iPALF; 3 had moderate and 3 had minimal staining pattern (per table 2). The dense CD8+ pattern was seen in 3 of 9 with autoimmune hepatitis and in 1 of 14 with other liver diseases.
E-D Pfister et al. Liver Transplantation 2018; 24: 1186-98. This study examined patient (n=338) and graft survival in the pediatric population (median age 14.0 years) with Wilson’s disease (1968-2013). Overall, patient survival was 87% at 1 year, 84% at 5 years, and 81% at 10 years. Though, the survival was much improved since 2009.
JA Bezzerra et al. Hepatology 2018; 68: 1163-73. This review summarized a research workshop (June 2017) focused on the clinical and research challenges for biliary atresia.
VL NG et al. J Pediatr 2018; 196:139-47. This study with 148 children examined the neurodevelopmental outomes of young children with biliary atresia (ChiLDRen Study). Key finding: Children with their native livers were at increased risk for neurodevelopmental delays at 12 and 24 months. This risk was more than 4-fold increased among those with unsuccessful Kasai procedure.
WS Lee et al. J Pediatr 2018; 196: 14-20. Updated review on hepatopulmonary synddrome (HPS) and portopulmonary hypertension (POPH). Figure 1 graphically shows the difference in pathophysiology. HPShallmark is intrapulmonary vascular dilatation. POPH is characterized by progressive remodeling of the wall (thickening & vasoconstriction) of small pulmonary arteries.
JA Woo Baidal et al. Hepatology; 2018; 67: 1339-47. This prospective cohort study with 528 children showed that increased Vitamin E intake in early childhood, based on validated food questionnaires, correlated with lower ALT values in mid-childhood. Children with higher intakes “had lower odds of elevated mid-childhood ALT” (adjusted odds ratio of 0.62) when comparing quartiles 2-4 to the lowest quartile. The authors note that Vitamin E is present in foods that are more often consumed in “healthful diets, such as wheat germ, almonds, spinach, and broccoli, as well as cooking oils.”
J Pfeiffenberger et al. Hepatology 2018; 67: 1261-69. The retrospective multicenter study with 282 pregnancies in 136 women with Wilson’s disease (WD), showed good outcomes. Aggravation of neurologic symptoms was rare (1%) (though tended to persist), liver test abnormalities (6%) resolved in all cases after delivery. Birth defect rate of 3% and spontaneous abortion rate of 26%; rthough, patients receiving treatment with zinc and D-penicillamine had lower spontaneous abortion rates, (10% and 17%, respectively) than those without treatment. Chelation therapy resulted in no increase in the rate of birth defects compared to the general population.
F Bril et al. Clin Gastroenterol Hepatol 2018; 16: 558-66. This prospective study of adults with biopsy-proven NASH (52 with diabetes and 49 with prediabetes) found that pioglitazone treatment was associated with a reduction in the primary outcome, NAFLD activity score by 2 or more points, in 48% of those with type 2 diabetes and 46% of those with prediabetes. And, with a resolution of NASH in 44% and 26% respectively.
P Socha et al. JPGN 2018; 334-4. This ESPGHAN position paper makes recommendations for Wilson’s disease. This is a helpful paper, though the AASLD Wilson’s guideline is more comprehensive. A couple of pointers from the JPGN publication:
The authors recommend molecular testing if available and using liver copper measurement “if molecular testing is inconclusive”
Screen siblings of any new patients
Urinary copper excretion in the 200-500 mcg per 24 hours is consistent with adequacy of treatment
With treatment, liver function tests improve over 2-6 months. “If increased transaminases remain or relapse despite treatment, poor compliance should be suspected.”
A study from France (R Santiago et al. JPGN 2015; 61: 613-18) examined the use of zinc therapy for Wilson’s disease. Though the national survey had 90 children from 6 centers, there were only 26 who were treated with zinc and only 9 who had received zinc as a first-line single therapy.
Despite the small numbers, data on treating children with Wilson’s disease are fairly sparse; as such, this article provides some helpful information.
The study reviews zinc’s mechanism of action:
“Oral zinc induces enterocyte synthesis of metallothionein, a cystic-rich protein acting as an endogenous chelator for metals, which preferentially binds copper in the enterocyte and inhibits its entry into the portal circulation. Thereby, it reduces copper intestinal absorption and leads to copper elimination in fecal contents within senescent enterocytes.”
“Median transaminase level normalized within 6 months from treatment initiation” in the entire cohort of 26 children. However, 10 of 26 children had abnormal ALT at 6 months into therapy.
Zinc dose was gradually increased such that 38% eventually had doses “exceeding recommended doses” which were >75 mg/day in 6-15 years and >150 mg/day in those ≥16 years.
Overall, the authors thought that zinc appeared to be less effective. Failure with zinc occurred in 5 of 9 (3 due to ineffectiveness, 2 due to poor adherence). The authors note that decompensation has been reported in children and adults on zinc monotherapy.
The authors indicate that zinc therapy is likely most appropriate after an induction phase with chelators in most children. Criteria for changing to zinc include the following: “patients should be clinically well…with normal transaminase levels and hepatic synthetic function, non-ceruloplasmin-bound copper concentration within the normal range, and 24-hour urinary copper excretion in the range of 200-500 mcg/24 h.”
Additional precautions with zinc acetate (which is often better tolerated than chelators), 4 of 26 children in this study had gastric irritation, including one child with a perforation. Therefore, a low threshold for endoscopy should be set in a child with epigastric pain. Adherence can be problematic due to the timing & frequency (TID) of zinc administration. Monitoring urinary zinc excretion can be useful to monitor compliance.
When I read a recent Hepatology editorial (Hepatology 2015; 61: 1106-8), I could not help think of the aforementioned title of this blog.
Here’s the scoop:
The two most commonly used medications for Wilson’s disease are trientine (Syprine) and D-penicillamine (Cupramine). For about 20 years, the original manufacturer of these medications kept the consumer cost at ~$1 per 250 mg tablet. Currently the cost of Syprine is ~$200 per 250 mg tablet and Cuprimine costs ~$55 per 250 mg tablet. This 200-fold increase translates into a yearly cost of ~$300,000.
How did this happen?
Patients are reluctant to protest (they need this medication to be manufactured)
Why is this outrageous?
This increase in cost was not driven by any new discovery or research innovation.
Are there options?
Zinc is inexpensive and may be an option after initial period of chelation/normalization of liver biochemistries. Zinc needs to be taken two to three times per day and “well away from meals for best absorption.”
Bottomline: These medication prices are outrageous.
“Molecular pathophysiology of portal hypertension” Hepatology 2015; 61: 1406-15. Terrific review with excellent figures.
“Ezetimibe for the treatment of Nonacloholic Steatohepatitis” (MOZART trial) Hepatology 2015; 61: 1239-50. This randomized double-blind, placebo-controlled trial with 50 patients (biopsy-proven NASH) showed that Ezetimbe was not significantly different from placebo in histologic response rates, serum aminotransferases, or in magnetic resonance elastography findings.
Van Biervliet et al. “Clinical Zinc Deficiency as Early Presentation of Wilson Disease” JPGN 2015; 60: 457-9. Case report.
A recent clinical problem-solving case report highlights the fact that seeing the right specialist helps a great deal with pattern recognition (NEJM 2013; 368: 1345-51). In this report, intriguingly titled “The Essential Element” the authors describe a 21-year-old who presented with refractory hemolytic anemia along with low albumin, low alkaline phosphatase, and elevated total & direct bilirubins. Her course was somewhat protracted due to treatment of hemolytic anemia and lack of recognition of underlying hepatocellular disease. After readmission three months later the diagnosis of Wilson’s disease was made and quickly she underwent orthotopic liver transplantation.
A couple of pointers from this article for me included the following:
Parenchymal injury from the oxidative effect of copper leads to the hepatocellular injury. Release of copper also causes oxidative damage of erythroctye membranes.
The low alkaline phosphatase which is characteristic of Wilson’s is potentially due to the oxidative damage from free radicals or by competition at the active site of the alkaline phosphatase enzyme.
The combination of hemolysis with liver dysfunction should prompt consideration of Wilson’s.
Most hepatologists would quickly recognize the pattern presented in this case report. Getting the patient to the right physician is the key.