A Mysterious Rise in LFTs

Transcription

1 Bita V. Naini, M.D. UCLA David Geffen School of Medicine Disclosure of Relevant Financial Relationships USCAP requires that all faculty in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Naini declares he/she has no conflict(s) of interest to disclose. Clinical history 10 year old previously healthy female was transferred to UCLA for transplant evaluation for acute liver failure. She was in her usual state of health until ~10 days prior when she started to complain of cough and had low grade fever. Multiple family members have been ill with URI, sinusitis and congestion. Over the course of the week, she became more tired and not acting like herself, and presented to the ER with N/V and altered mental status. Clinical history Medication: Prescription: Keflex (Cephalexin) OTC: Zyrtec (cetirizine) Tylenol and Aspirin Zarbee s No significant PMH No family history of genetic disorders or early childhood death Laboratory Data ALT 857 AST 372 Alk phos 219 Bilirubin 1.2 INR 1.5 Ammonia 429 Clinical Differential Diagnosis Viral hepatitis (systemic viruses) Non-infectious hepatitis: Drug induced liver injury (DILI) (e.g. acetaminophen) Herbal/supplement induced liver injury (SILI) Autoimmune (AIH) Metabolic disorders Wilson s disease 1

2 Laboratory Data Infectious etiologies: Negative for Hep A/B/C, EBV, Enterovirus, CMV, HHV-6, Parvo B19, HIV, HSV /supplements toxicity: Acetaminophen level negative Salicylate level negative Urine tox negative for benzos, cocaine, amphetamines, cannabinoid, opiate, barbiturate, tricyclics Zarbee s: honey and melatonin Autoimmune hepatitis: Autoimmune serology negative Wilson s disease: Ceruloplasmin normal 24 hour urine copper normal A liver biopsy was performed Minimal to no inflammation or necrosis Steatosis 2

3 Amoeba Amoeboid mitochondria Enlarged, swollen and irregular The cristae are fragmented and reduced Matrix is rarified/clear due to absent of dense granules Final diagnosis: A Mysterious Reye s in LFTs Extensive microvesicular steatosis with mitochondrial abnormality, consistent with Reye s syndrome Steatosis terminology Macrovesicular steatosis Large droplet Small droplet Microvesicular steatosis 3

4 Differential diagnosis Macrovesicular steatosis Increased triglyceride synthesis or decreased excretion. Obesity and diabetes mellitus and toxins (e.g. alcohol) Protein-calorie malnutrition Metabolic disorders (e.g. Wilson s disease) Infection (e.g. hepatitis C, genotype 3) Large droplet vs Small droplet Relevant to suitability for liver donation MaS >30% is an independent predictor of reduced 1 yr graft survival Inborn errors of metabolism (e.g. inherited mitochondrial cytopathies, fatty acid oxidation disorders) Valproic acid, IV tetracycline, zidovudine (nucleoside analog), etc Inborn errors of metabolism (e.g. inherited mitochondrial cytopathies, fatty acid oxidation disorders) Valproic acid, IV tetracycline, zidovudine (nucleoside analog), etc Acute fatty liver of pregnancy and alcoholic foamy degeneration are linked to mitochondrial dysfunction AFLP is linked to both genetic and acquired factors that compromise mitochondrial function and FAO [Natarajan SK, Hepatology, 2010]. The incidence is increased in women who carry a fetus with defect in FAO or who are themselves carriers of a genetic mutation that compromises their own mitochondrial FAO [Treem WR, Semin Gastrointestin Dis, 2002]. Some patients with alcoholic foamy degeneration have been found to have a deletion in the hepatic mitochondrial DNA oxidative damage to mitochondria [Mansouri et al, Journal of Hepatology, 1997]. Inborn errors of metabolism (e.g. inherited mitochondrial cytopathies, fatty acid oxidation disorders) Valproic acid, intravenous tetracycline, zidovudine (nucleoside analog), etc Jamaican Vomiting Sickness Vomiting and encephalopathy Toxin hypoglycin A (HGA) in unripe fruit of ackee tree. When ingested, HGA is converted to a metabolite that inhibits the ß-FAO. The levels of HGA is markedly reduced upon ripening, so that mature fruits contain only trace amount, and are safe for consumption. 4

5 A similar outbreak of lethal encephalopathy was observed in India for the past few years. Recently linked to consumption of lychee fruit in Muzaffarpur, India. Urinalysis of children affected has shown elevated levels of hypoglycin. Inborn errors of metabolism (e.g. inherited mitochondrial cytopathies, fatty acid oxidation disorders) Valproic acid, intravenous tetracycline, zidovudine (nucleoside analog), etc Reye s syndrome Serious and rapidly progressive encephalopathy with liver dysfunction Almost exclusively in children. While a few adult cases have been reported over the years, these cases do not typically show permanent neural or liver damage. It is typically preceded by a viral infection (e.g. influenza or varicella) Reye s syndrome History The first description in 1963 by Ralph Reye, a pathologist from Sydney, Australia. 21 children All presented with elevated liver enzymes and encephalopathy. Clinically preceded by malaise, mostly associated with URI. 17 died within the first days after admission a clinicopathologic entity of unknown etiology not convinced that the etiology is identical in every case. Reye s syndrome The rise and fall Reye s syndrome The rise and fall In the 1970s-80s several thousand cases were identified. Early reports showed an association between taking aspirin for viral illnesses. Led to a worldwide discontinuation of aspirin use for childhood viral illnesses. Large decline in incidence in 1980s-90s. Aspirin ad from 1953 Many patients later found to have undiagnosed genetic disorders, particularly in the pathway of mitochondrial FAO. A retrospective study of 26 survivors of cases diagnosed as Reye's Syndrome : 18 (69%) had various metabolic disorders, particularly a FAO disorder [Orlowski JP, Crit Care Med. 1999] Aspirin served as a triggering factor in metabolic decompensation rather than the root cause Aspirin alters mitochondrial FAO [Uppala, et al. Biochem Biophys Res. 2017] 5

6 Inborn errors of metabolism Pathophysiology of Reye s syndrome Environmental factors (toxins, drugs e.g. aspirin) pharmacogenetic susceptibility [Adapted from Schror. Pediatr Drugs 2007] Virus Altered immune response (immunogenetic susceptibility) Mitochondria Recovery Damaged Mitochondrial mitochondria damage Disturbance in mitochondrial metabolism Release of inflammatory cytokines (e.g. TNFα) and other mediators Metabolic failure and elevation of toxic metabolites (e.g. ammonia) Image Courtesy of Dr. Charlie Lassman Reye s syndrome Rare, but is it on the rise? Acetaminophen is a leading cause of unintentional drug overdose and acute liver failure. 6

7 Clinical history in our case Patient s mom gave her Tylenol on the first day she got sick but then given her concern for Tylenol toxicity gave her Aspirin for the next 7 days. Case follow up Patient was diagnosed with Reye s syndrome and encephalopathy. VP shunt was placed to relieve intracranial pressure. Unfortunately she had cerebral edema and suffered severe brain damage and was discharged to skilled facility. Whole genome sequencing didn t reveal any abnormalities. Follow-up at 1 year: non-verbal, not able to follow motor commands, dependent for feeding, limited motor function ability Reye s syndrome Prognosis Death occurs in 30-40% of those affected. About 1/3 of those who survive are left with a significant degree of brain damage. Early diagnosis based on clinical findings and liver biopsy, followed by supportive care, improves outcomes. Important Information Regarding CME/SAMs The Online CME/Evaluations/SAMs claim process will only be available on the USCAP website until September 30, No claims can be processed after that date! After September 30, 2017 you will NOT be able to obtain any CME or SAMs credits for attending this meeting. 7