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Disclosure of Relevant A Mysterious Rise in LFTs 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 Bita V. Naini, M.D. 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. UCLA David Geffen School of Medicine Dr. Naini declares he/she has no conflict(s) of interest to disclose.

A Mysterious Rise in LFTs

Clinical history Clinical history

• 10 year old previously healthy female was transferred to UCLA for • : transplant evaluation for acute failure. . Prescription: . Keflex (Cephalexin) • She was in her usual state of health until ~10 days prior when she started to . OTC: complain of cough and had low grade . . Zyrtec (cetirizine) . Tylenol and • Multiple family members have been ill with URI, sinusitis and congestion. . Zarbee’s

• Over the course of the week, she became more tired and “not acting like • No significant PMH herself,” and presented to the ER with N/V and altered mental status. • No family history of genetic disorders or early childhood

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Laboratory Data Clinical Differential Diagnosis • Viral hepatitis (systemic viruses) ALT 857 AST 372 • Non-infectious hepatitis: • Drug induced liver injury (DILI) (e.g. acetaminophen) Alk phos 219 • Herbal/supplement induced liver injury (SILI) Bilirubin 1.2 • Autoimmune (AIH) INR 1.5 • Metabolic disorders Ammonia 429 • Wilson’s disease

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Laboratory Data • Infectious etiologies: • Negative for Hep A/B/C, EBV, Enterovirus, CMV, HHV-6, Parvo B19, HIV, HSV

• Drugs/supplements toxicity: • Acetaminophen level negative A liver was performed • 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

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Minimal to no or necrosis

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Amoeba

Amoeboid mitochondria • Enlarged, swollen and irregular • The cristae are fragmented and reduced • Matrix is rarified/clear due to absent of dense granules

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Steatosis terminology Final diagnosis: A Mysterious “Reye’s” in LFTs Macrovesicular steatosis Large droplet Small droplet Microvesicular steatosis Extensive microvesicular steatosis with mitochondrial abnormality, consistent with Reye’s syndrome

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Differential diagnosis – Macrovesicular steatosis Differential diagnosis – Microvesicular Steatosis

• Increased triglyceride synthesis or decreased excretion. • Mitochondrial damage leading to impaired fatty acid β-oxidation (FAO) • Obesity and diabetes mellitus • Reye’s syndrome • Drugs and toxins (e.g. alcohol) • Acute fatty liver of pregnancy (AFLP) • Protein-calorie malnutrition • Alcoholic foamy degeneration • Metabolic disorders (e.g. Wilson’s disease) • Toxins (e.g. Jamaican sickness) • Infection (e.g. hepatitis C, genotype 3) • Inborn errors of metabolism (e.g. inherited mitochondrial cytopathies, fatty acid oxidation disorders) Large droplet vs Small droplet • Drugs • Relevant to suitability for liver donation • Valproic acid, IV tetracycline, zidovudine (nucleoside analog), etc • MaS >30% is an independent predictor of reduced 1 yr graft survival

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Differential diagnosis – Microvesicular Steatosis Acute fatty liver of pregnancy and alcoholic foamy degeneration are linked to mitochondrial dysfunction • Mitochondrial damage leading to impaired fatty acid β-oxidation (FAO) • AFLP is linked to both genetic and acquired factors that • Reye’s syndrome compromise mitochondrial function and FAO [Natarajan SK, • Acute fatty liver of pregnancy (AFLP) Hepatology, 2010]. • The incidence is increased in women who carry a fetus with defect in FAO • Alcoholic foamy degeneration or who are themselves carriers of a genetic mutation that compromises their • Toxins (e.g. Jamaican vomiting sickness) own mitochondrial FAO [Treem WR, Semin Gastrointestin Dis, 2002]. • Inborn errors of metabolism (e.g. inherited mitochondrial cytopathies, fatty acid oxidation disorders) • Some patients with alcoholic foamy degeneration have been found • Drugs to have a deletion in the hepatic mitochondrial DNA  oxidative damage to mitochondria [Mansouri et al, Journal of Hepatology, 1997]. • Valproic acid, IV tetracycline, zidovudine (nucleoside analog), etc

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Differential diagnosis – Microvesicular Steatosis Jamaican Vomiting Sickness • Mitochondrial damage leading to impaired fatty acid β-oxidation (FAO) • Reye’s syndrome • Vomiting and • Acute fatty liver of pregnancy (AFLP) • Toxin hypoglycin A (HGA) in unripe fruit of • Alcoholic foamy degeneration ackee tree. • Toxins (e.g. Jamaican vomiting sickness) • When ingested, HGA is converted to a • Inborn errors of metabolism (e.g. inherited mitochondrial metabolite that inhibits the ß-FAO. cytopathies, fatty acid oxidation disorders) • The levels of HGA is markedly reduced • Drugs upon ripening, so that mature fruits • Valproic acid, intravenous tetracycline, zidovudine (nucleoside contain only trace amount, and are safe analog), etc for consumption.

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Differential diagnosis – Microvesicular Steatosis

• Mitochondrial damage leading to impaired fatty acid β-oxidation (FAO) • Reye’s syndrome • Acute fatty liver of pregnancy (AFLP) • Alcoholic foamy degeneration • Toxins (e.g. Jamaican vomiting sickness) • Inborn errors of metabolism (e.g. inherited mitochondrial cytopathies, fatty acid oxidation disorders) • Drugs

• A similar outbreak of lethal encephalopathy was observed in India for the past few years. • Valproic acid, intravenous tetracycline, zidovudine (nucleoside • Recently linked to consumption of lychee fruit in Muzaffarpur, India. analog), etc • Urinalysis of children affected has shown elevated levels of hypoglycin.

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Reye’s syndrome – History Reye’s syndrome • The first description in 1963 by Ralph Reye, • Serious and rapidly progressive encephalopathy with liver a pathologist from Sydney, Australia. • 21 children dysfunction • All presented with elevated liver enzymes and encephalopathy. • Almost exclusively in children. While a few adult cases have been • Clinically preceded by malaise, mostly reported over the years, these cases do not typically show associated with URI. permanent neural or liver damage. • 17 died within the first days after admission •a “clinicopathologic entity of unknown etiology” • It is typically preceded by a viral infection (e.g. or varicella) •“…not convinced that the etiology is identical in every case…”.

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Reye’s syndrome – The rise and fall Reye’s syndrome – The rise and fall • In the 1970s-80s several thousand cases • Many patients later found to have undiagnosed genetic disorders, were identified. particularly in the pathway of mitochondrial FAO. • A retrospective study of 26 survivors of cases diagnosed as • Early reports showed an association “Reye's Syndrome”: 18 (69%) had various metabolic disorders, between taking aspirin for viral illnesses. particularly a FAO disorder [Orlowski JP, Crit Care Med. 1999] • Led to a worldwide discontinuation of • Aspirin served as a triggering factor in metabolic decompensation aspirin use for childhood viral illnesses. rather than the root cause • Large decline in incidence in 1980s-90s. • Aspirin alters mitochondrial FAO [Uppala, et al. Biochem Biophys Res. 2017] Aspirin ad from 1953

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Pathophysiology of Reye’s syndrome [Adapted from Schror. Pediatr Drugs 2007] Environmental factors (toxins, Inborn errors of drugs e.g. aspirin) – Virus metabolism pharmacogenetic susceptibility Altered immune response (immunogenetic susceptibility)

Release of DamagedMitochondrial inflammatory Mitochondria mitochondriadamage cytokines (e.g. TNFα) and other mediators Disturbance in Recovery mitochondrial metabolism

Metabolic failure and elevation of toxic metabolites (e.g. ammonia)

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Image Courtesy of Dr. Charlie Lassman

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Reye’s syndrome – Rare, but is it on the rise?

•Acetaminophen is a leading cause of unintentional and acute .

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Clinical history in our case Case follow up • Patient was diagnosed with Reye’s syndrome and encephalopathy. VP shunt was placed to relieve intracranial “Patient’s mom gave her Tylenol on the first pressure. Unfortunately she had and suffered severe and was discharged to skilled facility. day she got sick but then given her concern for Tylenol toxicity gave her Aspirin for the • Whole genome sequencing didn’t reveal any abnormalities. next 7 days.” • Follow-up at 1 year: non-verbal, not able to follow motor commands, dependent for feeding, limited motor function ability

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Important Information Reye’s syndrome – Prognosis Regarding CME/SAMs • Death occurs in 30-40% of those affected. The Online CME/Evaluations/SAMs claim process will only be • About 1/3 of those who survive are left with a significant degree available on the USCAP website until September 30, 2017. of brain damage. No claims can be processed after that date!

• Early diagnosis based on clinical findings and liver biopsy, After September 30, 2017 you will NOT be able to obtain any followed by supportive care, improves outcomes. CME or SAMs credits for attending this meeting.

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