drug induced liver disease
DILD is caused by many different drugs of mostly painkillers and fever reducers which contain acetaminophen drug this is hepatotoxic because drugs are absorbed by liver on high dose of this drug lead damage of liver known as liver injury. Rarely absorbed in children. actually people who drink alcohol has high prone to drug injury, but in children in happened because of antiepileptic and antiniotics.the antibiotics most often implicated with liver injury are amoxicillin/clavulanic acid, flucloxacillin and erythromycin .Nonalcoholic Fatty Liver Disease (NAFLD) is the most common forms of chronic liver disease in children and adolescents. It is an inherited disorder that affects the metabolism – the way the body breaks food down into energy.Drug-induced liver injury in children (cDILI) accounts for about 1% of all reported adverse drug reactions throughout all age groups, less than 10% of all clinical DILI cases, and around 20% of all acute liver failure cases in children. The overall DILI susceptibility in children has been assumed to be lower than in adults. Nevertheless, controversial evidence is emerging about children's sensitivity to DILI, with children's relative susceptibility to DILI appearing to be highly drug-specific. The culprit drugs in cDILI are similar but not identical to DILI in adults (aDILI). This is demonstrated by recent findings that a drug frequently associated with aDILI (amoxicillin/clavulanate) was rarely associated with cDILI and that the drug basiliximab caused only cDILI but not aDILI. The fatality in reported cDILI studies ranged from 4% to 31%. According to the US Food and Drug Administration-approved drugs labels, valproic acid, dactinomycin, and ampicillin appear more likely to cause cDILI. In contrast, deferasirox, isoniazid, dantrolene, and levofloxacin appear more likely to cause aDILI. Animal models have been explored to mimic children's increased susceptibility to valproic acid hepatotoxicity or decreased susceptibility to acetaminophen or halothane hepatotoxicity. However, for most drugs, animal models are not readily available, and the underlying mechanisms for the differential reactions to DILI between children and adults remain highly hypothetical. Diagnosis tools for cDILI are not yet available. A critical need exists to fill the knowledge gaps in cDILI. This review article provides an overview of cDILI and specific drugs associated with cDILI.
Out of 298 patients enrolled 273 (92%) resolved ⩽1 year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR:1.06, p=0.011], dyslipidemia [OR:4.26, p=0.04] and severe DILI [OR:14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 xULN and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p<0.001)
DILI is possible consequence of ingestion of OTC drugs like PCM.
so it require careful clinical knowledge before taking drugs without doctors prescriptions...
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Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
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2. Incidence
10 fold increase in No. of reported cases between
1964-1973 in Japan
10% of cases of hepatitis in a major hepatology
center in France
20% of instances of jaundice among geriatric
population in USA
9% of hospitalized patients with AST ≥ 400 IU/L
in a survey in UK
25%-40% of fulminent hepatic failure
3. Drug-induced Liver Disease (DILD)
Predictable
• Dose related
• Intrinsically hepatotoxic drugs
• Acute (hours)
• Injury pattern is usually necrosis
• Clinically → Fulminant (Acute Hepatitis)
• Example: Acetaminophine
Unpredictable
• Not dose related
• Rare 0.01-1.0 %
• Weeks to months after ingestion of drug
• Idiosyncratic
Immune mediated idiosyncrasy (Hypersensitivity)
• Rash
• Fever
• Arthragia
• Eosinophilia
• Example: Phenytoin, Sulfonamides, Valproate
Metabolic idiosyncrasy (Production of toxic metabolites)
• Example: INH, Ketoconazole, and Diclofenac
4. Overview of Drug induced Liver Injury
Types of Drug Reactions
Approach to the patient
Natural History
6. Categorization according to type of reaction
Direct toxic reactions
Idiosyncratic reactions
Combined toxic/Allergic reactions
Allergic hepatitis
Cholestatic reactions
Granulomatous reactions
Chronic hepatitis and cirrhosis
Fatty liver /NASH
Veno-Occlusive disease
Neoplastic
7. Diagnosis of (DILD)
High index of suspicion
Abnormalities in hepatic associated enzymes
Hepatitis like symptoms
Jaundice
Drug history
• Dose
• Duration of therapy
• Time between initiating therapy and the development of
hepatic injury (latency)
Exclusion of other causes of liver diseases
• Hepatitis B
• Hepatitis C
• Alcoholic liver diseases
• Non alcoholic fatty liver diseases
• Hemochromatosis
2%-5% of
general
population
8. Diagnosis of (DILD)
Temporal relationship
• Most cases of acute DILD occurring within 1 week to
3 months of exposure
• Positive response to discontinuing the agent
(Dechallenge)
In acute hepatocelluler injury
• 50% reduction in hepatic –associated enzymes after 2 weeks
• Return to normal by 4 weeks
In cholestatic injury
• May have prolonged recovery time
10. Risk Factors For Susceptibility to DILD
Methotrexate
• Alcohol
• Obesity
• D.M
• Chronic hepatitis
INH
• HBV,HCV,HIV
• Alcohol
• Older age
• Female
Acetaminophen
• Alcohol
• Fasting
• INH
Valproate
• Young age
• Anticonvulsants
Diclofenac
• Female
• Osteoarthritis
11. Risk Factors For Susceptibility to DILD
Sulfonamide
• HIV
• Slow acetylator
• Genetic defect in
defense
Anticonvulsats
• Genetic defect in
detoxification
Rifampicin
• Slow acetylators
• INH
Pyrazinamide
• Slow acetylators
• INH
12. Clinical Presentations
Asymptomatic elevation in hepatic enzymes
No progress despite
Continued use of the
Medication.
(Drug tolerance)
•INH
•Phenytoin
•Chlopromazine
Progression to
Hepatic injury with
Continued use of the
medication
AST & ALT 3-5 times
Upper limit of normal
May progress to
Hepatic failure
13. Acute Hepatocelluler Injury
(Direct toxic reaction)
Characterized by
• Marked elevation in ALT and AST
• Normal or minimally elevated alkaline phosphatase
• Bilirubin variably increased-----›worse prognosis.
Comprise 1/3 of all cases of fulminant hepatic
failure in the US.
• 20% due to Acetominophen
• 12%-15% due to other drugs
14. Acute Hepatocelluler Injury
(Direct toxic reaction)
Alcohol
• AST is always 2-3 times higher than ALT
• AST remains less than 300 IU.
• ALT is almost always less than 100 IU.
Towering elevation of ALT&AST(5000-10000 IU)
• Drugs (acetaminophen)
• Differential:
Chemical toxins
Toxic Mushrooms
Shock liver
• Unusual with other causes of liver diseases including
Viral Hepatitis.
16. Cholestatic Injury
Definition: Reduction in bile flow due to
• Reduced secretion
• Obstruction
Biochemically:
• Elevated Alk phosphatase
• Elevated GGT
• Elevated 5 NT
Acute illness that subsides when the offending drug
is withdrawn.
20. Comparison between PBC with DICC
PBC DICC
Gender women both
Age Middle-aged All ages
AMA Positive Negative
Onset Insiduous Acute
Jaundice Late feature Acute feature
Pruritis + +
Hypercholestremia + +
Steatorrhea + +
Xanthomas + +(transient)
VBDS + +
Portal infiltrates +++ +
Granulomas + -
Prognosis Often progresses to billiary
cirrhosis
Jaundice usually resolves after
6-76 m;rarely progresses to
billiary cirrhosis
PBC : Primary billiary cirrhosis DICC :Drug induced chronic cholestasis
21. Granulamatous Hepatitis
A form of hepatic injury characterized by :
• Fever
• Diaphoresis
• Malaise
• Anorexia
• Jaundice
• Rt upper quadrant discomfort
• Granuloma on liver biopsy
• Illness usually occurs within the first 2 months of therapy
Examples:
• Quinidine
• Carbamazipine
• Allopurinol
• Hydralazine
• Phenytoin
• Gold
• Mineral oil ingestion
• Phenylbutazone
22. Drug induced chronic hepatitis
Can resemble chronic active hepatitis including cirrhosis as well as
a form of chronic autoimmune hepatitis
Characteristics of drug- induced autoimmune hepatitis
Duration of drug intake ≥ 2-24 months
Female predominance > 80%
Onset Insidious, gradual
Clinical Fatigue, anorexia, wt loss, jaundice,
ascites, hepatosplenomegaly, and portal
hypertension
Biochemical AST, ALT= 5-50 × ULN
Increased gamma globulin level
Serology
AICH 1
AICH 2
ANA, ASMA, LE factor
Anti-P4501A2, AntiP4502C9
Histology Very active necro-inflammatory lesion
Prominent plasma cells
Usual course Resolution on withdrawal of drug
23. Drugs leading to a syndrome resembling
type I autoimmune chronic hepatitis
Multiple cases
Drugs Serologic Factors
Clometacin ASMA, Anti-DNA
Methyldopa ANA(16%), ASMA(35%)
Minocycline ANA, Anti-DNA
Nitrofurantoin ANA(80%), ASMA(72%)
Oxyphenisatin ANA(67%), ASMA(67%), LE(33%)
Few cases
Benzarone ASMA
Diclofenac ANA
Fenofibrate ANA
Papverine ANA, ASMA
Pemoline ANA, Automicrosomal antibody
Propylthiouracil ANA
Captopril ANA, Antilaminin
Flucloxacillin AMA,(Anti-M2)
Procainamide ANA, LE factor(50-70%)
24. Vascular injury
May involve all of the vascular components of the liver,
including the sinusoids, hepatic veins, and hepatic arteries.
Veno-occlusive disease (VOD):
• May be caused by:
Toxic plant alkaloids (certain herbal tea)
A serious complication complication of bone marrow transplant
• Azathioprine is probably the calprit
• Clinically presents as
Mild vral-like illness →→ Fulminent hepatic failure
Rapid weight gain
Ascites
Jaundice
Evidance of portal hypertension
Chronic form of VOD may also exist.
26. Natural History and Prognosis
When recognized promptly and the offending agent is
discontinued most cases resolve without chronic sequalae
Mortality principally depend on the degree of hepatocelluler
injury.
10% mortality for agents causing fulminant hepatitis or
toxic steatosis.
Agents that cause cholestatic injury rarely , if ever ,
produce acute fatalities
The prognosis is worse whenever jaundice accompanies
hepatocelluler injury.