The document discusses the liver's role in drug metabolism and detoxification. It outlines two main pathways - phase 1 involves activation via cytochrome P450 enzymes which can make substances more toxic, while phase 2 involves conjugation via enzymes like UDP-glucuronosyl transferase to make substances more water soluble and able to be excreted. Many dermatologic drugs can cause hepatotoxicity through idiosyncratic or intrinsic mechanisms. Ketoconazole notably carries a risk of hepatotoxicity and fulminant hepatitis. The liver's role in drug interactions is also reviewed.

1. Dermatologic TherapeuticsDermatologic Therapeutics
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the Liverthe Liver
Hossam Ghoneim, MD
Cairo University

2. OutlineOutline
• Background
§ Liver functions
§ Detoxification pathways in the liver
§ Pharmacologic implications of hepatic metabolism
§ Role of hepatic metabolism in drug interactions
• Drug induced hepatotoxicity
§ Overview
§ Factors influencing susceptibility
§ Pathophysiologic mechanisms
§ Clinicopathological patterns
• Dermatology drugs & the liver
• Diagnosis of Hepatotoxicity
• Treatment of Hepatotoxicity

3. Liver FunctionsLiver Functions
• Metabolic (homeostasis, regulating energy balance)
§ Carbohydrate metabolism
§ Fat metabolism
§ Protein metabolism
• Synthetic
§ E.g. Albumin and Prothrombin
• Detoxification
§ Drugs
§ Toxins
§ Products of metabolism (e.g. urea & ammonia)

4. Liver Detoxification PathwaysLiver Detoxification Pathways
• Inside the liver cells there are sophisticated
mechanisms to break down toxic substances.
• Every drug, artificial chemical, pesticide and
hormone, is broken down (metabolized) by enzyme
pathways inside the liver cells.
• Many of the toxic chemicals that enter the body are
only fat-soluble.
• This makes them difficult for the body to excrete.

5. The Liver Detoxification PathwaysThe Liver Detoxification Pathways
• Fat soluble chemicals have a high affinity for fat tissues
and cell membranes, which are made of fatty substances.
• In these fatty parts of the body, toxins may be stored for
years, being excreted during times of exercise & fasting.
• During release of these toxins, symptoms like headache,
poor memory, nausea, fatigue & dizziness may occur.
• The liver has two mechanisms designed to convert fat-
soluble chemicals into water soluble chemicals
facilitating easy excretion from the body via watery fluids
such as bile and urine.

6. How does the Liver DetoxifyHow does the Liver Detoxify
Harmful Substances?Harmful Substances?

7. First Pass MechanismFirst Pass Mechanism
• Phase 1 reactions
§ Mainly for activation (yielding active intermediate metabolites)
§ Cytochrome P-450 mediated (many isoenzymatic substrates)
§ Primarily oxidative in nature (i.e. maybe in itself toxic)
§ Products of this step usually undergo further
metabolism via phase 2 reactions
§ Thus phase 1 may be regarded as potential
“toxification” while phase 2 as “detoxification”.

8. First Pass MechanismFirst Pass Mechanism
(note about CYP(note about CYP--450)450)
§ CYP450s are mainly in hepatocytes, but also cells of the kidney, lung,
intestine, skin, testis, brain
§ Each CYP450 oxidises many substrates (with some selectivity)
§ nomenclature of CYP450s:
• Example P4502E1
§ first number (i.e. "2") refers to CYP family (>40% homology)
§ capital letter (i.e. "E") refers to subfamilies (>60% homology)
§ second number (i.e. "1") refers to a particular P450 isoform
§ major human cytochrome P450s (also called hepatic mono-oxygenases)
• Example CYP1A2
§ is expressed universally in liver tissue
§ metabolises drugs such as: caffeine, theophylline, phenacetin by dealkylations
§ also activates aromatic amino procarcinomages

9. Second Pass mechanismSecond Pass mechanism
• Phase 2 reactions
§ Mainly conjugation, converting active metabolite to non
toxic more hydrophilic products to be excreted through bile
or kidney
• glucuronidation - transfer of glucuronic acid to drug
§ enzyme involved: UDP-glucuronosyl transferase
§ cofactor required: UDP-glucuronic acid
• sulphation - transfer SO3- to drug
§ enzyme involved: sulfotransferase
§ cofactor required: PAP-sulphate
• acetylation (transfer of acetyl group to drug)
§ enzymes involved: N-acetyltransferase
§ cofactor required: acetyl CoA
• glutathione conjugation (add glutathione to drug)
§ enzyme involved: glutathione-S-transferase
§ cofactor required: glutathione

10. Pharmacological implications of drugPharmacological implications of drug
metabolismmetabolism
• Modification by phase I and phase II reactions usually
alters the pharmacological properties of the agent
§ pharmacological deactivation
• most drug metabolites exhibit less affinity for relevant receptors,
thus biotransformation usually implies pharmacological deactivation
• biotransformation also typically generates metabolites that are more
easily cleared from the body, further diminishing the duration of a
drug's action
§ pharmacological activation
• for a few drugs, inactive prodrugs undergo metabolism within the
body to active drugs

11. Role of hepatic metabolism in drugRole of hepatic metabolism in drug
interactionsinteractions
• knowing the metabolic fate of drug is important
§ It can help avoid adverse effects due to drug interactions during
treatment with 2 or more drugs
• example: ketoconazole is metabolised by a specific CYP450 (3A4) and can
inhibit the clearance of terfenadine which is a substrate for the same
CYP450 (hence cardiac toxicity) “Torsade de point”
§ Prolonged exposure to some drugs can cause over expression of
CYP450s (induction) causing a loss of potency of other drugs that are
metabolized via that isoform
• example: barbiturates induce specific CYP, and ethinylestradiol
(contraceptive) is metabolised by this CYP, and so is metabolised too
quickly (therefore ineffective) if patient is taking barbiturates

12. DrugDrug--induced hepatotoxicityinduced hepatotoxicity
OverviewOverview
• Accounts for
§ 2-5% of all cases of Jaundice in hospitalized patients
§ 40% of hepatitis cases over 50yrs
§ 25% of cases of fulminant hepatitis
• Spectrum of disease ranges from subclinical to
subfulminant or even fulminant hepatitis requiring
liver transplantation.
• It can mimic any type of liver disease.
• Early recognition is essential since morbidity is
greatly increased if the drug is continued.
• OTC medications & herbal remedies may have
profound hepatotoxicity & their use should be
rationalized.

13. Factors influencing susceptibility toFactors influencing susceptibility to
hepatotoxicityhepatotoxicity
• Age
• Underlying liver disease (subtle or overt)
• Nutritional status
• Gender
• Ethnic & racial factors
• Pregnancy
• Duration & total dose of drug
• Drug-drug interactions

14. Characterization of hepatotoxicityCharacterization of hepatotoxicity
• Intrinsic hepatotoxicity
§ May occur secondary to metabolic mediated hepatocellular necrosis or
interference with specific hepatocellular pathways.
§ Leads to structural architectural injury thus disruption of excretory
pathways → cholestasis.
§ Almost always dose-dependant
§ Famous e.g. Acetaminophen and alcohol.
• Idiosyncratic hepatotoxicity
§ Unexplained reaction to some drugs
§ Not dose-dependant
§ May be part of an immunologic reaction with other systemic
manifestations.
§ Usually develop after a sensitization period of several weeks.
§ E.g. Isonizid, Valproate, phenytoin and sulphonamides.

15. Drug Induced HepatotoxicityDrug Induced Hepatotoxicity
PathophysiologicPathophysiologic mechanismsmechanisms
• Disruption of the hepatocyte
§ Covalent binding of the drug to intracellular proteins can cause a
decrease in ATP levels, leading to actin disruption. Disassembly of actin
fibrils at the surface of the hepatocyte causes blebs and rupture of the
membrane.
• Disruption of the transport proteins
§ Drugs that affect transport proteins at the canalicular membrane can
interrupt bile flow. Loss of villous processes and interruption of
transport pumps such as multidrug resistance–associated protein 3
prevent the excretion of bilirubin, causing cholestasis.
• Cytolytic T-cell activation
§ Covalent binding of a drug to the P-450 enzyme acts as an immunogen,
activating T cells and cytokines and stimulating a multifaceted immune
response.

16. Drug Induced HepatotoxicityDrug Induced Hepatotoxicity
PathophysiologicPathophysiologic mechanismsmechanisms
• Apoptosis of hepatocytes
§ Activation of the apoptotic pathways by the tumor necrosis factor-alpha
receptor of Fas may trigger the cascade of intercellular caspases, which
results in programmed cell death.
• Mitochondrial disruption
§ Certain drugs inhibit mitochondrial function by a dual effect on both
beta-oxidation energy production by inhibiting the synthesis of
nicotinamide adenine dinucleotide and flavin adenine dinucleotide,
resulting in decreased ATP production.
• Bile duct injury
§ Toxic metabolites excreted in bile may cause injury to the bile duct
epithelium

17. Drug Induced HepatotoxicityDrug Induced Hepatotoxicity
ClinicopathologicalClinicopathological patternspatterns
• Hepatocellular (necroinflammatory) → ALT/AST
§ Inflammation (hepatitis – acute, chronic or fulminant)
§ Steatosis or steatohepatitis
§ Granulomatous à ALP
• Cholestatic → BIL/ALP/ GGT/ERCP
§ PBS
§ Sclerosing cholangitis
• Mixed (hepatocellular & cholestatic) → All LFTs
§ Autoimmune hepatitis
• Vascular (e.g. VOD & Budd-chiari) → Imaging
• Neoplastic (Hepatoma, FNH, etc.)→ Imaging/ a fetoprt.

19. Dermatology drugsDermatology drugs
andand
the liverthe liver
Zoom in

20. Drugs used in DermatologyDrugs used in Dermatology
• Antifungal drugs
• Antibacterial drugs
• Antiviral drugs
• Corticosteroids
• Drugs affecting skin differentiation and proliferation
• Immunosuppressive and immunomodulatory agents
• Anti-inflammatory drugs
• Paracetamol
• Antipruritic drugs
• Astringents
• Scabicides and pediculicides
• Ultraviolet blocking agents

21. Antifungal drugsAntifungal drugs
• Benzoic acid with salicylic acid
• Miconazole nitrate
• Selenium sulfide
• Sodium thiosulfate
• Ketoconazole
§ It can cause inconsequential biochemical abnormalities with a
necroinflammatory pattern in as many as 3-10% of patients taking it.
§ It is thought to be due to an idiosyncratic mechanism occurring mainly
in middle aged women.
§ several instances of fulminant hepatitis have been recorded.
• Fluconazole
§ It has been associated with modest aminotransferase elevation.
§ Some reports of fatal hepatic necrosis were reported.

22. Antibacterial drugs
• Methylrosanilinium chloride
• Potassium permanganate
• Neomycin with bacitracin
• Silver sulfadiazine
• Tetracycline
§ Acute direct hepatocellular toxicity.
• Penicillin and Amoxicillin-Clavulanic acid
§ Necroinflammatory > cholestatic (mixed).
• Erythromycin
§ Cholestatic Jaundice> ↑ALP and bilirubin.
• Trimethoprim-Sulfamethoxazole
§ Cholestatic (may last for months).

23. Antiviral AgentsAntiviral Agents
• Zidovudine
§ Sporadic cases of biochemical hepatitis.
• Didanosine
§ Elevated transaminases, especially in high doses.
• Interferon alpha
§ It may provoke deterioration of hepatic enzymes when used
for treatment in patients with autoimmune hepatitis.

24. Corticosteroids
• Betamethasone
• Hydrocortisone acetate
§ Flare of viral hepatitis if present à Necroinflammatory.
§ Macrovesicular steatosis.
• Anabolic and Androgenic steroids:
§ Hepatoma.
§ Peliosis Hepatis.

25. Drugs affecting skin differentiation
and proliferation
• Fluorouracil
§ Cream, fluorouracil 5%
§ Rare hepatotoxicity.
• Salicylic acid
§ Topical solution (Cutaneous solution), salicylic acid 5%
§ Ointment , salicylic acid 1–6% [not included on WHO Model
List]
§ Hepatotoxicity is dose dependent à topical salicylates are not
potential hepatotoxic substances.

26. ImmunomodulatorsImmunomodulators
• Cyclosporine
§ powerful immunosuppressive drug with no appreciable effect on the
bone marrow
§ Mechanism of action:
• T-cell dependent and T-cell independent effects.
• It basically modulates immune cell function by inhibiting calcineurin-
dependent dephosphorylation-activation of specific nuclear factors, thus
preventing transcription of pro-inflammatory cytokines.
• In stimulated T cells, this drug inhibits activation by suppressing IL-2
production and IL-2R expression.
• Cyclosporine also inhibits chemokine production by human mast cells,
antigen presentation by Langerhans cells and neutrophil chemotaxis.
§ Infrequent hepatotoxicity.
§ Usually cholestasis with prominent hyperbilirubinemia.
§ Mediated by inhibition of canalicular bile acid transport.

27. ImmunomodulatorsImmunomodulators
• Mycophenolate mofetil (MMF) Celesept
§ Mechanism of action:
• Selectively inhibits inosine monophosphate dehydrogenase
(IMPDH).
• It also induces apoptosis of activated T cells, decreases the
recruitment of lymphocytes and induces immune tolerance.
§ Drug interaction:
• Because of its high affinity for plasma albumin, MPA competes with
other drugs such as salicylates and furosemide that are bound to
albumin; concurrent administration may lead to an accelerated
elimination.
• As MMF and azathioprine block purine synthesis by inhibiting the
same enzyme (IMPDH), MMF should not be used in combination
with azathioprine
§ MMF may prove to be beneficial especially for patients who
are not suited to other systemic immunotherapies because of
hypertension, impaired renal function or liver disease.

28. ImmunomodulatorsImmunomodulators
• Leflunomide
§ antiviral, antitumorigenic, and immunosuppressive
properties.
§ It inhibits autoimmune T-cell proliferation and production
of autoantibodies by B-cells.
§ Dosage:
• Because of the long half-life of its active metabolites,
treatment is initiated at a dose of 100 mg once daily for 3
days and continued with 10-25 mg daily.
§ Adverse effects:
• Gastrointestinal symptoms are the most common
adverse effects.

29. ImmunomodulatorsImmunomodulators
• Tacrolimus
§ Mechanism of action:
• Active against helper T cells, preventing the production of IL-2 via
calcineurin inhibition (binds to tacrolimus-binding protein instead of
cyclophilin protein).
§ Adverse effects:
• Adverse effects include nephrotoxicity, neurotoxicity, glucose
intolerance, and QT prolongation (rare).
• Tacrolimus causes fewer cosmetic effects than cyclosporine, but it
can cause reversible alopecia.
§ Drug-drug interaction:
• Multiple drug interactions are possible, primarily with agents
affecting the cytochrome P-450 system.

30. Immunosuppressive AgentsImmunosuppressive Agents
• Methotrexate
§ Psoriasis à hepatic steatosis, fibrosis and cirrhosis are “not
uncommon”
§ Cumulative dose increases risk.
§ Total dose of 1.5 g is associated with significant liver
disease.

31. Immunosuppressive AgentsImmunosuppressive Agents
• Azathioprine
§ Wide range of hepatotoxic reactions including nodular
regenerative hyperplasia, veno-occlusive disease, and most
commonly cholestasis.
§ Usual asymptomatic aminotransferases elevation.
§ Presumed mechanism of action of hepatotoxicity is via
damage of endothelial cells within terminal hepatic venules
and sinusoids.

32. AntiAnti--inflammatory Drugsinflammatory Drugs
• Overall, extremely low incidence of NSAID-induced
hepatotoxicity BUT extremely common use increases risk.
• Diclofenac (Voltaren)
§ Mixed hepatocellular/cholestatic picture.
§ More in elderly women.
• Sulindac (Clinoril)
§ 50% à cholestatic pattern.
§ More in elderly women.
• Piroxicam (Feldene)
§ Less frequently encountered hepatotoxicity.

33. ParacetamolParacetamol
• Acetaminophen
§ Fulminant hepatic failure in up to 30%.
§ Overdose is the most common cause of drug induced
hepatotoxicity
• Amount ingested as a single dose require to produce
hepatic injury may be 10-20 g.
• Alcoholism is a significant risk factor (therapeutic dose
can cause hepatotoxicity)
§ Prognosis of fulminant hepatitis in such case is poor
§ Liver transplantation is almost always needed

34. Zoom out
Drug induced hepatotoxicityDrug induced hepatotoxicity
DiagnosisDiagnosis
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TreatmentTreatment

35. DrugDrug--Induced HepatotoxicityInduced Hepatotoxicity
DiagnosisDiagnosis
• Single agent vs. multiple agents
• History including dose, route of administration, duration, previous
administration, and use of any concomitant drugs, including OTC
medications and herbs ingested in the past 3 months is essential.
§ Onset: The onset is usually within 5-90 days of starting the drug.
§ Exclusion of other causes of liver injury/cholestasisis essential.
• Dechallenge test
• Rechallenge test

36. DrugDrug--Induced HepatotoxicityInduced Hepatotoxicity
DiagnosisDiagnosis
• Lab. tests to assess and diagnose the effects of the suspected medication is
essential.
• Hepatocellular process generally have a disproportionate elevation in serum
aminotransferase levels compared with alkaline phosphatase levels, while
those with cholestasis have the opposite findings.
• The presence of antibodies to specific forms of CYP
• Lymphocyte transformation to test drugs may be observed for drugs acting
through immunologic reactions, but this is not commonly used.

37. DrugDrug--Induced HepatotoxicityInduced Hepatotoxicity
DiagnosisDiagnosis
• Hepatic function tests and their interpretations
§ Bilirubin (total) - To diagnose jaundice and assess severity
§ Bilirubin (unconjugated) - To assess for hemolysis
§ Alkaline phosphatase - To diagnose cholestasis and infiltrative disease
§ AST/serum glutamic oxaloacetic transaminase (SGOT) - To diagnose
hepatocellular disease and assess progression of disease
§ ALT/serum glutamate pyruvate transaminase (SGPT) – more specific for acute
hepatocellular injury
§ Albumin - To assess severity of liver injury
§ Gamma globulin - Large elevations suggestive of autoimmune hepatitis, other
typical increase observed in persons with cirrhosis
§ Prothrombin time after vitamin K - To assess severity of liver disease
§ Antimitochondrial antibody - To diagnose primary biliary cirrhosis
§ ASMA - To diagnose primary sclerosing cholangitis

38. DrugDrug--Induced HepatotoxicityInduced Hepatotoxicity
DiagnosisDiagnosis
• Imaging studies
§ Ultrasonography: inexpensive compared with CT scanning
and MRI and not time consuming.
§ CT scanning
§ MRI
• Liver biopsy
§ Histopathologic evaluation remains an important tool in
diagnosis. A liver biopsy is not essential in every case, but a
morphologic pattern consistent with the expected pattern
provides supportive evidence.

39. Drug Induced HepatotoxicityDrug Induced Hepatotoxicity
TreatmentTreatment
• Early recognition of drug-induced liver reactions
• For drugs that produce liver injury unpredictably, biochemical monitoring
is less useful.
• ALT values are more specific than AST values.
• ALT values that are within the reference range at baseline and rise 2- to 3-
fold should lead to enhanced vigilance in terms of more frequent
monitoring.
• ALT values 4-5 times higher than the reference range should lead to prompt
discontinuation of the drug.

40. Drug Induced HepatotoxicityDrug Induced Hepatotoxicity
TreatmentTreatment
• No specific treatment. Largely supportive and symptomatic.
• First step is to discontinue the suspected drug.
• N-acetylcysteine in the early phases of acetaminophen toxicity.
• L-carnitine is potentially valuable in cases of valproate toxicity.
• In general, corticosteroids have no definitive role in treatment.
• Management of drug-induced cholestasis similar to PBC.
• Cholestyramine may be used for alleviation of pruritus.
• Ursodeoxycholic acid may be used.
• Lastly, consulting a hepatologist can be helpful.

41. Take home messageTake home message
• Egyptian livers are particularly vulnerable
§ LFT’s/Viral markers may be recommended prior to treatment
§ History of liver disease is very important
• Monitor level in blood whenever possible
• Early suspicion & recognition is crucial
• Dechallenge test is helpful
• Target all LFT’s and US if in doubt of specific tests
• Liver supportive measures should be started early
• Hepatology consultation is “round the corner”

42. Thank YouThank You