JB Talcott et al. JPGN 2019; 69: 145-51. This small study showed an association with prolonged cholestastic liver disease in children and poorest cognitive outcomes despite successful transplantation. There were 28 participating children in this study, only 12 with chronic liver disease. Acute liver disease was not associated with deficits in cognitive function. This study “reinforces the need for timely intervention.”
AA Butt et al. Gastroenterol 2019; 156: 987-96. This study which used a Veterans database for chronic hepatitis C (HCV) infection (n=242,680) found that treatment with direct-acting antiviral therapy (hazard ratio 0.57) was associated with a significant decrease in risk of cardiovascular disease events.
F DiPaola et al JPGN 2019; 69: 152-59. This study from the drug induced liver injury (DILI) network (2004-2017) with just 57 cases found that antimicrobials (51%) and antiepileptics (21%) were the leading causes of DILI in children. Related blog: Liver toxicity –Where to Look Online
P Huelin et al. Hepatology 2019; 70: 319-33. This study with 320 consecutive cases of acute kidney injury (AKI) in patients hospitalized for cirrhosis found that urinary neutrophil gelatinase-associated lipocalin (NGAL) (best at day 3) helped differentiate acute tubular necrosis from other types of AKI.
A recent study (J Ahmad et al. Clin Gastroenterol Hepatol 2019; 17: 789-90) reviewed subjects in enrolled in drug-induced liver injury (DILI) prospective cohort to determine the frequency of sclerosing cholangitis (SC)-like changes in this population. SC-like changes have previously been noted in up to 10% of DILI cases (Dig Liv dis 2015; 47: 502-7). In this study, 233 of 1487 subjects had underwent an MRI.
- Four of 56 (7%) with adequate quality images had SC-like images (4 with intrahepatic stricture and 1 with a common hepatic duct stricture as well)
- Patients with SC-like changes had a more severe initial injury noted and were more likely to develop chronic injury as noted by persistent lab abnormalities at 6 months
My take: This study indicates that a severe DILI can result in secondary sclerosing cholangitis.
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A Benesic et al. Clin Gastroenterol Hepatol 2018; 16: 1488-94. This prospective study found that monocyte-derived hepatocyte-like (MH) cells isolated from patients could be used to test and identify drugs that triggered acute liver injury. Among 40 patients, 13 patients had 10 drugs identified which were toxic to MH cells. Overall, they reported the MH test as having a 92% sensitivity and 100% specificity.
I Medina-Caliz et al. Clin Gastroenterol Hepatol 2018; 16: 1495-1502. Using the Spanish DILI registry (1994-2016), the authors identified 32 of 856 cases of DILI that were due to dietary supplements. Patients were more often female (63%), and had a mean ALT level 37-fold above ULN. 3 patients (9.4%) progressed to acute liver failure. Many of these supplements were promoted as helpful for weight loss. The authors speculate that reported cases of DILI due to herbal supplements are ‘the tip of the iceberg’ due to under-reporting of cases.
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Lake Moraine, Banff
A recent study (EK Hsu et al. Gastroentorol 2017; 153: 988-95, editorial 888-89) exposes some deep flaws in organ transplantation in U.S.
The retrospective study examined children on the U.S liver transplant wait-list from 2007-14. This included 3852 pediatric candidates. Key findings:
- Of 27,831 adults who underwent transplantation, 1667 (6%) received livers from pediatric donors (<18 years)
- Of children who died or were delisted, the centers caring for 173 (55%) had received an offer of 1 or more livers that was subsequently transplanted into another pediatric recipient. The remaining 45% died or delisted with no offers. High-volume (>15 transplants per year) centers were more likely to accept an organ than a low-volume center (<5 transplants per year).
- Only 29% of children received a split graft. When a splittable adult liver graft was allocated to an adult the chance of it being used as a split was 0.6%.
- Children have much lower survival rate than adults on waiting list. Of adults who died or delisted, 85% receive at least one transplant offer; whereas, nearly half of all children never even receive an offer. Children who died/delisted had wait-time of 33 days compared with 92 days for adults who died/delisted.
- Less than 10% of all liver transplant recipients are pediatric transplants. Per editorial, “a measure that improves pediatric access by 20% would only reduce adult access by 2%.”
- There are more than 100 pediatric liver transplant centers in U.S. Certainly, this improves convenience; however, per editorial: “three-fourths are very low volume centers, performing <5 liver transplantations per year…Death on waiting list” occur 5 times more at low-volume transplantation centers.
- In this study, only 29% of children received split livers; in comparison, in the UK, >80% receive either a split graft or living donor graft.
The editorial points out that splittable livers that are allocated to adults are virtually never split; this is either due to inconvenience or lack of expertise. A small increase in liver splitting would dramatically lower the pediatric mortality wait list. There is no incentive in the current system to split a liver/save a child’s life.
My take: The data from this study points out glaring problems in pediatric liver transplantation.
- Children are dying due to lack of prioritization. Pediatric livers are going to adults.
- There is practically no splitting when liver organs are allocated to an adult. Incentives to increase organ splitting would save many children from dying waiting for an organ.
- Large volume pediatric centers are much more likely to accept a liver offer for patients waiting at their centers. There is an increased wait-list mortality at very low volume centers, perhaps due to lack of expertise and passing up viable organs. Do hepatologists/surgeons at these centers explain this risk to families at their centers?
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A recent study (H Devarbhavi et al. Hepatology 2016; 63: 993-99 & associated editorial 700–2) provide insight into outcomes and causative agents in patients who had both drug-induced liver injury (DILI) along with severe skin reactions.
With regard to the skin reactions, the authors were specifically focused on Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). SJS indicates an area of skin detachment of <10% and TEN involves >30%. SJS/TEN overlap is 10-30%.
The study reviewed a single center DILI registry over 18 years with 748 patients. There was prospective recruitment during the final 10 years of the study period (1997-2015). 36 (4.8%) had either SJS or TEN (mean age 32 years, 53% females). 9/36 (25%) were <18 years.
- Antiepileptics 47%
- Sulfonamides 18%
- Nevirapine 16%
- Multiple agents 61%
- Median duration between drug initiation and onset of rash was 24 days
- 13/36 (36%) died. 77% of those who died had jaundice.
- 14/36 (39%) received steroids including 10 survivors and 4 who died.
While a mortality of 36% among those with both DILI and SJS/TEN is high, the discussion notes that the mortality is high even in those without DILI (~18% in ones study). There were 8/36 in the study with HIV which is associated with a much higher risk of DILI. There was a lower mortality in the pediatric age group (1 child 11%) and in those with HIV (1 patient 12.5%).
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Walnut Street Bridge
A recent study (VL Re et al. Clin Gastroenterol Hepatol 2015; 13: 2360-68) examined a retrospective cohort of 15,353 patients with presumed drug-induced liver injury (DILI) to formulate a more sensitive model for predicting liver failure.
The authors note that Hy’s Law has good specificity but poor sensitivity. In their population, Hy’s Law had a specificity of 0.92, negative predictive value of 0.99, sensitivity of 0.68, and a positive predictive value of 0.02.
- Hy’s law (named for Hyman Zimmerman): AST or ALT > 3 ULN and total bilirubin ≥2 ULN indicate serious hepatotoxicity with >10% mortality rate.
By incorporating data from platelet count and total bilirubin, the authors devised a Drug-Induced Liver Toxicity ALF Score which had a high sensitivity of 0.91 but a lower specificity of 0.76.
- DrILTox ALF Score = -0.00691292*platelet count + 0.19091500*total bilirubin (per mg/dL)
- Example: platelet count of 145 & total bilirubin of 3.0 yields a valued of -0.4296 which is above cut off of -1.081 indicating an increased risk of ALF.
Thus, low platelet counts and high bilirubins are strong predictors of acute liver failure (ALF) in the setting of DILI.
My take: Overall, the incidence of ALF due to drugs remains fairly low and determining that a specific drug induced liver injury remains problematic. This study shows that ALF can occur in those who do not meet Hy’s Law criteria and that more sensitive predictors are needed.
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Two recent studies provide complementary information regarding the causes and consequences of Drug-Induced Liver Injury (DILI).:
- Chalasani N, et al. Gastroenterol 2015; 148: 1340-52.
- Goldberg DS, et al. Gastroenterol 2015; 148: 1353-61.
The first study looked at 899 patients with DILI in the DILI Network which is a consortium of several academic institutions funded by the US National Institutes of Health. Antimicrobials were the most commonly implicated agents (408 cases); however, dietary/herbal supplements were another common cause (145 cases). Top 10 individual agents:
- Amoxicillin-clavulanate (Augmentin) (n=91)
- Isoniazid (n=48)
- Nitrofurantoin (n=42)
- Sulfamethoxazole/trimethoprim (n=31)
- Minocycline (n=28)
- Cefazolin (n=20)
- Azithromycin (n=19)
- Ciprofloxacin (n=16)
- Levofloxacin (n=13)
- Diclofenac (n=12)
- Overall, 10% of patients with DILI died or required liver transplantation.
- 18% developed chronic injury pattern; this was more common in patients with a cholestatic liver injury.
- Mortality was high in patients with DILI and concomitant severe skin reactions. Causative agents of DILI with either Stevens-Johnson Syndrome or Toxic epidermal necrolysis included azithromycin (n=2), lamotrigine (n=3); and one case for each of the following: moxifloxacin, diclofenac, carbamazepine, nitrofurantoin, and possible cephalexin (patient rec’d lamotrigine as well)
- Preexisting liver disease increased the likelihood of mortality (16% versus 5%)
The second article, a retrospective cohort study using data from >5 million covered individuals over a 7-year span from Kaiser Permanente Northern California, identified 62 inpatients categorized as having definite or possible acute liver failure (ALF). In this cohort, 32 (52%) had DILI. Leading agents of DILI-ALF:
- Acetaminophen n=18
- Herbal/dietary supplement n=6. Chinese herbals (n=2), pine needle tea, saw palmetto, one unspecified herbal.
- Antimicrobials n=2
Bottomline: Antibiotics and herbal supplements, both of which are often used without apparent benefit, can lead to liver failure
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Soapes Creek, Atlanta
A useful review on the hepatobiliary manifestations of inflammatory bowel disease (IBD): Inflamm Bowel Dis 2014; 1655-67.
A few topics/comments from review:
Primary sclerosing cholangitis (PSC):
- “among those with PSC, about 70% to 80% have UC and 15% to 20% have CD. Those IBD patients with PSC are more likely to develop malignant complications and to require liver transplantation. Conversely, only about 0.4% to 7.5% of patients with IBD will develop PSC.”
- “Currently, no medical treatment has been proven to decrease the progression of PSC.”
- “At the time of diagnosis of PSC, IBD must be ruled out and a complete colonoscopy with multiple segmental biopsies of the mucosa needs to be performed.” Among PSC-IBD patients, “annual surveillance colonoscopy is recommended.”
- Further surveillance recommendations (eg. annual imaging/CA 19-9 annually) discussed in Table 2.
Cholelithiasis: Gallstones are reported in 13% to 24% of all patients with CD. In UC, the risk of cholelithiasis “does not seem to be increased.”
Drug-induced liver disease: (see liver tox website)
- Biologic agents
Viral hepatitis in immunosuppressed IBD patients:
Hepatitis B reactivation -algorithm for screening/management of latent hepatitis B provided in Figure 3
Other liver problems seen in IBD patients:
- Portal Vein Thrombosis
- Nonalcoholic Fatty Liver Disease
- Secondary amyloidosis
- Hepatic abscess
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Using a population-based cohort, the authors of a recent study from Iceland performed a prospective study, collecting data on 96 individuals with drug-induced liver injury (DILI) from 2010-2011 (Gastroenterol 2013; 144: 1419-25 & editorial 1335-36). This study benefitted from a centralized medical care system with about 250,000 adults. Patients with acetaminophen toxicity were excluded.
- DILI occurred in 19 cases per 100,000 persons per year. This is higher than previous DILI estimates in other populations and may be due to identifying more subclinical cases.
- DILI increased markedly with age from 9 per 100,000 among 15-29 year olds to 41 per 100,000 among those >70; however, this paralleled the increase use of medications.
- Eight drugs were implicated in more than 1 case with subsequent risk estimates:
- Augmentin 1 per 2350 users
- Azathioprine 1 per 133 (mostly anicteric cases)
- Infliximab 1 per 148
- Nitrofurantoin 1 per 1369
- Isotretinoin 1 per 732
- Atorvastatin 1 per 3693
- Diclofenac 1 per 9148
- Doxycycline 1 per 16,339
Some commonly implicated drugs did not show up on the list: fluoroquinolones, macrolide antibiotics, minocycline, valproic acid, and cancer chemotherapeutic agents (except one case due to imatinib). The editorialist notes that these agents are not commonly used in Iceland. Also, 16% of cases were due to herbals and dietary supplements.
Consequences of DILI: 27% developed jaundice, 12% required hospitalization, and 1 patient died. The median time for liver tests to normalize in those that recovered was 64 days.
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While anti-TNF agents have been associated with drug-induced liver injury (DILI), it has been difficult to get a handle on how much importance to place on this. A recent study provides more data and some reassurance (Clin Gastroenterol Hepatol 2013; 11: 558-64).
The authors searched the U.S. DILI Network database from 2003 to 2011 and describe 6 cases of anti-TNF DILI; in addition, they searched PubMed for articles related to anti-TNF agent associated hepatotoxicity and identified an additional 28 cases. Other causes of liver disease were excluded in these patients, including reactivation of hepatitis B, and acute viral hepatitis (eg. hepatitis C, hepatitis E).
Results of anti-TNF hepatotoxicity:
- 26 cases due to infliximab, 4 cases due to etanercept, and 4 due to adalimumab.
- Based on scoring system, the anti-TNF agent was considered a definite cause of DILI in 1 (3%), very likely in 21 (62%) and probable in 12 (35%).
- Median latency (duration of therapy before onset of DILI) was 13 weeks with a range of 2-104 weeks.
- 22 (67%) had positive anti-nuclear and/or smooth muscle antibodies. 15 of 17 of these patients had liver biopsy features consistent with autoimmunity.
- Among those 22 with autoimmune features, there was a higher peak alanine aminotransferase compared with the 12 without these features (784 vs 528 U/L)
- Favorable outcome: all but one patient improved after discontinuation of the implicated drug; 12 received corticosteroids. One patient with underlying cirrhosis underwent liver transplantation after infliximab-induced liver injury.
While the authors note the potential for a class effect of anti-TNF agents, in studies from patients with psoriasis, there was a lack of cross-toxicity between etanercept and infliximab.
The risk of hepatocellular injury from anti-TNF agents is very low. DILI due to anti-TNFs often have autoimmune features. The prognosis is favorable, and alternative anti-TNFs can be given after resolution.
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