REGIONAL HOSPITAL BAMENDAWEEKLY SCIENTIFIC MEETING
Thursday, 19 July2018
- THE INFECTIOUS DISEASE UNIT
Team : - Dr Leo N.Ayuk
- Dr Makebe Haman
- EM7 Toukam Daniele
- MrEbai Bisong Takor
- Supervision: - Pr Kuaban Christopher
- Dr Kinge Thompson
OUTLINE OF THEPRESENTATION
- Functioning of the Unit
- Statistics 1stSemester2018
- Case presentation
- Nursing Care Plan
- Literature Review
- Drug induced hepatotoxicity, now retermed Drug‐induced liver injury (DILI) is a problem of increasing significance, but has been a long‐standing concern in the treatment of tuberculosis (TB) infection.
- The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury.
- Antituberculosis drug‐induced hepatotoxicity (ATDH) causes substantial morbidity and mortality and diminishes treatment effectiveness.
- Understanding of TB DILI (ATDH) has been hampered by differences in study populations, definitions of hepatotoxicity, and monitoring and reporting practices.
THE INFECTIOUS DISEASEUNIT:
- Receives exclusively patients with bacteriologically proven TB and exceptionally other TB patients who are severely ill.
THE INFECTIOUS DISEASE UNIT
TB ward with Bed Capacity: 32beds
-1 Female ward for drug sensitive TB: 10beds
-1 Male ward for drug sensitive TB: 10beds.
- 4 rooms of 3 beds each for Drug resistantTB.
TB unit which receive all patients followed on outpatient basis and does drug dispensationandpaperwork.
TB reference Laboratory performing a wide range of laboratory investigations (GenXpert, Viral Load, LPA, Liquid Culture, Fluorescence Microscopy, PCR, Hep B Viral Load, etc…..)
THE INFECTIOUS DISEASE UNIT STAFF SITUATION
- 4 Medical doctors.
- 3 senior Nurses
- 1 HNDNurse
- 3 Nurse assistants
- 1 Ward Maid.
NB: 60% of this staff are voluntary workers.
- Modern adapted building for care of TB patients.
- Well trained team of physicians.
- Good treatment success rates
- Devoted team of Nurses
- Good follow-up of patients.
- Regular training/refresher of the staff
- Regular ward meetings to discuss problems
- Lack of kitchen (for our patients who have to stay for long periods in the hospital)
- Lack of dedicated space for XDR-TB
- Insufficient workforce
- Insufficient drying line for patients.
Expert on TB and lung diseases.
- The TBRL (State of the art diagnostic tools)
- Support of the hospital administration
- Support of the Regional TB control Program.
- Presence in our team of an international
- Voluntary workers (60% of our staff)
- Security (Dilapidated fence behind the ward)
STATISTICS 1ST SEMESTER 2018
(NEW CASES NOTIFICATION)
||Bacteriologically positive cases
|Tt after failure
||Tt after default
STATISTICS 1ST SEMESTER 2018 (HIV TESTING)
|New cases SPPTB
STATISTICS 1ST SEMESTER 2018 (TREATMENT OUTCOME Q3 2017
All HIVpositive cases
By Dr Makebe.
- SB, 35 yrs old
- Business lady
- Resident in Dubai
HISTORY OF PRESENTING COMPLAINT
- Persistent right upper abdominal pain:2months duration
- The patient was in her usual state of health until 02 months prior to consultation when she developed a gradually increasing abdominal pain; right upper quadrant ,constant, not radiating, no aggravating nor relieving factor , severity of 7/10.
- It was associated with a progressive unquantified weight loss and occasional cough (productive of mucoid sputum without any hemoptysis) and night sweats. Chest pain(‐),dyspnea(‐)
- She took traditional concoctions for about a month to noavail.
- Persistence and worsening of the pain prompted the patient to return to Cameroon where she consulted at the BRH hospital and was admitted at the infectious disease unit.
- No known chronic illnesses, DM(‐), hepatitis(‐)
- Immuno Allergic: Diagnosed ID at entry, no known allergies
- Toxicology: tobacco(‐), alcohol (+):occasionally
- Social: does not remember contact with a TB patient.
- FAMILY: nil
SYSTEMIC ENQUIRY (At entry)
- General: anorexia(+),asthenia(+),weight loss(+),night sweats(+),fever(‐).
- Digestive: abdominal pain (+), jaundice (‐), generalized pruritus(‐),nausea(‐),vomiting(‐),abdominal distension(‐),early satiety(‐),coca cola colored urine (‐), discolored stool(‐).
- Cardiovascular: dyspnea(‐), palpitations(‐),orthopnea(‐)
- Nervous: paresthesia(‐),electrical discharges in the lower limbs(‐)
- Genitourinary:dysuria(‐),frequency(‐),hematuria(‐),per vaginal discharges(‐),
- Musculoskeletal: arthralgia(‐), myalgia(‐)
PHYSICAL EXAMINATION (Atentry)
- chronically ill‐looking
- Vital signs: BP=119/80mmHg , P=99 b/min T= 38 deg, RR=18c/min SPO2=98% Weight=71kg
Head and neck:
no nasal flaring, moderately colored conjunctivae, anicteric sclerae, presence of oral thrush, no cervical lymph node enlargement, no distension of jugular veins.
PHYSICAL EXAMINATION (cont’d)
- Symetrical chest wall, expansion and vocal fremitus
- Coarse crackles at the base of both lungs.
- S1/S2 heard, normal, no added sounds
PHYSICAL EXAMINATION cont’d)
- Non distended, moved with respiration.
- Tenderness at the right hypochondrium and epigastrium; liver span= 10 cm, smooth bordered without any palpable mass. No splenomegaly , skin turgor= Returns rapidly.
- Percussion note =tympanic
- Bowel sounds = Present and normal
PHYSICAL EXAMINATION (cont’d)
- No asymmetry, no tenderness on palpation or movement of any of the joints, reflexes ok
- A 35 year old female, who has a history of consumption of traditional concoctions, who does not recall to have been in contact with a TB patient, and she was newly diagnosed I.D. She presented with persistent right upper abdominal pain of 2 months duration.
- There were constitutional symptoms (anorexia, asthenia, night sweats, and weight loss).
- Physical examination revealed; a chronically ill‐looking patient with, moderately colored conjunctivae, coarse crackles at the base of both lungs, tender right hypochondrium and epigastrium without organomegaly.
Diagnosis and Differentials
- New case pulmonary tuberculosis in an ID patient
- R/O: disseminated tuberculosis hepatitis: viral, toxic, others
WORK‐UP and results(cont’d)
- Sputum analysis:2+,
- Xpert: MTB detected (medium)
- HIV test: POSITIVE
- FBC: microcytic normochromic anemia, Hb = 8.7g/dl
- AST/ALT: 87/ 45U/L
- Creatinine: 0.7mg/dl
- HbsAg and Hepatitis C:
- Diffuse reticulonodular opacities
- No pleural effusions
- No mediastinal lymph nodes
WORK‐UP and results (cont’d)
- Homogenous liver, no hepatomegaly
- Heterogeneous spleen of normal size,
- No deep abdominal lymph adenopathies,
- Kidneys of normal sizes and of normal differentiation
Non Pharmacological methods:
- Aim: Treat the infection and prevent complications
- Education and counseling of family members and patient+++
- Contact tracing
- Pyridoxine 50 mg tabs: 2‐0‐0/day(P.O)
- HAART (TDF‐3TC‐EFV): 0‐0‐1/day(P.O)
- Cotrimoxazole960 mg tabs: 0‐0‐1/ day(P.O)
- D1‐14: reduced cough, worsened right upper quadrant abdominal pain, gradual weight loss, onset of fever
IRIS (from initiation of HAART and RHEZ concomitantly)?
- D18: rapid onset of jaundice,
• AST/ALT: 128/243U/L
Hepatic failure (drug induced: RHEZ/ HAART)
- D21: agitation and incoherent speech
Ccl: Hepatic failure complicated by hepatic encephalopathy?
HAART (Efavirenz) – induced neuropsychosis?
- Stop all hepatotoxic drugs (RHEZ/HAART)
- Mannitol 10%: 100cc every 6 hours (IV line)
- Largactil 25 mg tabs: 1‐1‐1/ day(P.O)
- Vitamin C 1000mg tabs: 1‐0‐0/day(P.O)
- Serial weekly controls of AST/ALT
gradual decrease of jaundice, gradual improvements of AST/ ALT levels, absence of agitation, but patient had depressive behaviours (refusal to communicate, to accept condition, to continue taking medications)
Day 40: re‐introduction of RHEZ
Day 40‐54: continuous counseling, social workers and psychiatric nurses involved, serial AST/ALT controls: normal
Day 55‐65: clinical improvement
Day 65: discharged home
NURSING CARE PLAN
CASE: S.B 35yrs, Female, Old Town Bamenda.
PRESENTING: Anti TB Hepatotoxicity.
Weight loss, vomiting, watery stools,asthenia, nausea, anorexia
Fever, incoherent speech, agitations, drug refusal.
Model used forNCP: Virginia Avenel.H
||To eat and drink adequately
||Fluids, nutrients imbalance related to anorexia, vomiting and watery stools evidenced in weight loss and asthenia.
||Within 24 hours, patient should be able to eat and drink.
||−Encouraged much fluids intake
‐Daily mouth hygiene.
‐Encourage citreous fruits intake (rich in Vit C).
‐Educate family to prepare client best/balanced meals.
‐Monitor input/output and V/S
‐Seek medical attention and effect prescriptions
‐Stimulate taste buds, saliva promotion and hunger.
‐Increases desire to eat.
‐To be knowledgeable on the value of food nutrients.
|Within 24 hours, patient was able to eat and drink.
learn, discover or satisfy the curiosity that leads to normal development and health.
Deficit related to TB, HIV/AIDS
Evident by anxiety
Hours patient should be able to understand her condition and possible outcome.
‐Possible Side effects
Patient masters and understands disease condition and protocol.
‐Adhere to Rx
interventions, patient became calm and
Maintain normal body temperature.
Temperature related to infection evidenced by night fevers (temperature of
2 hours, temperature should be reduced
‐Open nearby windows.
‐serve drugs as prescribed
− I.E.C on temperature increase
heat loss by radiation, conduction and evaporation.
implementing the orders, temperature gradually reduced 38.5c.
Avoid dangers in the
environment, avoid injuring others and self
of injuries to self and others as evidenced by agitations and incoherent speeches
Prevent injuries to self and others
Harmful items around patient.
‐Served Rx as prescribed
- Increased bed/mattress surface area.
- Provided blockades.
- Informed the psychiatrist
‐Encourage much fluids and fruits intake
‐Monitor V/S closely
And report abnormalities from normal
‐To prevent accidents
‐To take appropriate measures.
−To detoxify the liver.
‐To detect abnormalities
- TB is the leading cause of death fromacurable infectiousdisease.
- About 11 million TB cases occurredworldwidein 2017 with 1.4 milliondeaths.
- In Cameroon, approximately 27000 TBcaseswere reported in 2017, with 1500 fromtheNWregion.
- The cornerstone of Tuberculosis management is a 6‐month course of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol.
- Compliance is crucial for curingTuberculosis.
- Adverse effects often negatively affect the compliance, because they frequently require a change of treatment, which may have negative consequences for treatment outcome
Outline of the presentation
- Case definition
- Pathology and clinical features
- Metabolism and mechanisms of toxicity of Isoniazid, Rifampicin and Pyrazinamide.
- Risk factors
- Many definitions for drug‐induced hepatotoxicity have been used in theliterature.
- It is difficult to define and diagnoseATDH,
because part of the definition is the exclusion of viral hepatitis or other possible causes of hepatotoxicity.
- There are numerous methods for assessing causality of adverse drug reactions, such as the chronology of the administration of the drugs, results of laboratory testing or the response to re‐administration of the drug.
- Histological findings (liver biopsy or autopsy) can support the diagnosis of drug‐induced hepatotoxicity
- A common definition of ATDH is a treatment‐emergent increase in serum alanine aminotransaminase (ALT) greater than three or five times the upper limit of normal, with or without symptoms of hepatitis, respectively.
- Symptoms of hepatitis include jaundice, abdominal pain, nausea, vomiting and asthenia.
Hepatotoxicity severity classification
WHO definition of hepatotoxicity
Grade 1 (mild) <2.5 times ULN (ALT 51–125U/L)
Grade 2 (mild) 2.5–5 times ULN (ALT 126–250U/L
Grade 3 (moderate) 5–10 times ULN (ALT 251–500U/L)
Grade 4 (severe) >10 times ULN (ALT > 500U/L)
- Table 1: Definition of hepatotoxicity according to the WHO Adverse Drug Reaction Terminology
- ALT, alanine aminotransferase; ULN, upper limit of normal, i.e. 50U/L
- Incidence varies between different world regions.
- 2‐28% in Europe, Asia, and USA.
- Higher rates in Indian patients.
- Sub‐saharan Africa: rates not reported (no LFT for routine monitoring of TB patients on therapy).
PATHOLOGICAL FEATURES (2)
- Isoniazid‐induced hepatotoxicity manifests mainly as hepatocellular steatosis and necrosis, and it has been suggested that toxic Isoniazid metabolites bind covalently to cell macromolecules.
- Hydrazine is the proposed toxic metabolite of Isoniazid and animal studies have shown that hydrazine causes steatosis, hepatocyte vacuolation and glutathione depletion.
- Lipid vacuoles and mitochondrial swelling is found in periportal and midzonal hepatocytes
- Rifampicin may cause transient hyperbilirubinemia, which is not a toxic effect but is due to interference with bilirubin excretion.
- Rifampicin can cause hepatic lesions characterized by hepatocellular changes, with centrilobular necrosis, possibly associated with cholestasis.
- Histopathological findings range from spotty to diffuse necrosis with more or less complete cholestasis.
- Bridging necrosis, lymphocytic infiltration, focal cholestasis, increased fibrosis, and micro nodular cirrhosis were observed in the liver of a patient who died of Rifampicin and Pyrazinamide‐induced hepatotoxicity.
- Hepatic drug reactions usually occur in the first 2 months of treatment but may happen at any moment during the treatment period.
- Clinical, biochemical and histological features of ATDH are hard to distinguish from viral hepatitis.
- The signs and symptoms of liver injury are jaundice, abdominal pain, nausea, vomiting and asthenia. They are not specific enough to ascertain a liver disorder.
- Therefore, confirmation by laboratory liver testing is required.
- Complaints of ATDH are mostly relieved when treatment is interrupted.
When treatment is not interrupted in time, ATDH can be fatal.
HEPATIC DRUG METABOLISM (2)
HEPATIC DRUG METABOLISM (1)
- The splanchnic circulation carries ingested drugs directly into the liver, a phenomenon known as the “first pass” through the liver.
- Metabolic enzymes convert these chemicals through phase 1 pathways of oxidation, reduction, or hydrolysis, which are carried out principally by the cytochrome P450 class of enzymes.
- Phase 2 pathways include glucuronidation, sulfation, acetylation, and glutathione conjugation to form compounds that are readily excreted from the body.
- Other subsequent steps include deacetylation and deaminidation. Many drugs may be metabolized through alternative pathways, and their relative contributions may explain some differences in toxicity between individuals.
- In phase 3 pathways, cellular transporter proteins facilitate excretion of these compounds into bile or the systemic circulation.
- Transporters and enzyme activities are influenced
by endogenous factors such as circadian rhythms,hormones,cytokines, disease states, genetic factors, sex, ethnicity,age, and nutritional status, as well as by exogenous drugs or chemicals.
- Bile is the major excretory route for hepatic metabolites.
- Compounds excreted in bile may undergo enterohepatic circulation, being reabsorbed in the small intestine and re‐entering the portal circulation
- Isoniazid is cleared mostly by the liver,primarily byacetylationbyN‐acetyltransferase2(NAT‐2).
- Acetyl‐isoniazid is metabolized mainly tomono‐acetyl hydrazine (MAH) and to the nontoxic diacetylhydrazine,aswellasotherminormetabolites.Interindividualvariationinplasmaeliminationhalf‐life(t1/2),independentofdrugdose and concentration, isconsiderable.
- Individuals with prolonged t1/2 have extendedexposure
tothedrug.GeneticpolymorphismsofNAT‐2correlatewithfast, slow, and intermediate acetylation phenotypes.
- Microsomal enzymes (e.g., cytochrome P450 2E1)further metabolize Isoniazid intermediates through phase 1pathways
ISONIAZID: METABOLISM (2)
- Acetylator status. In fast acetylators, more than 90% of the drug is excreted as acetyl‐Isoniazid, whereas in slow acetylators, 67% of the drug is excreted as acetyl‐Isoniazid and a greater percentage of Isoniazid is excreted as unchanged drug into the urine.
- However, fast acetylators clear MAH more rapidly. Slow acetylators may actually have greater cumulative MAH exposure.
- NAT‐2 genotyping by polymerase chain reaction recently demonstrated that slow acetylators experience transaminase elevations of more than three times the ULN more frequently than rapid acetylators (26 vs.11%).
- Slow acetylators also had higher peak ALT than did fast acetylators and, when rechallenged with Isoniazid, more frequently developed transaminase elevation of at least three times theULN.
ISONIAZID: MECHANISM OF TOXICITY (1)
- Reactive metabolites of MAH are probably toxic to tissues through free radical generation.
- In rats, the free radical scavenger glutathione‐related thiols, and antioxidant glutathione peroxidase and catalase activities, are diminished by Isoniazid, although glutathione reductase activity is increased.
- The antioxidant N‐acetyl‐cysteine, a substrate for glutathione synthesis, inhibits Isoniazid‐induced liver injury in pretreated rats, with unknown relevance in humans.
- Additional metabolic idiosyncratic mechanisms appear to be operative. The Isoniazid metabolite acetyl‐hydrazine covalently binds to liver macromolecules, a process mediated by microsomal enzymes.
- Patients with homozygous cytochrome P450 2E1 c1/c1 hostgenepolymorphism, who have enhanced cytochrome P450 2E1 activity, inonestudy had a higher risk of hepatotoxicity, particularly in slow acetylators.
- Rifampicin may occasionally cause dose dependent interference with bilirubin uptake, resulting in subclinical, unconjugated hyperbilirubinemia or jaundice without hepatocellulardamage.
- This may be transient and occur early in treatment or in some individuals with pre existing liver disease.
- Rifampicin occasionally can cause hepatocellular injury and potentiate hepatotoxicities of other anti‐TB medications.
- In a study of patients with brucellosis treated with the combination of rifampicin and minocycline, rifampicin‐attributed ALT increases of at least 250 IU/L were seen in approximately 5% ofpatients
RIFAMPICIN: MECHANISM OF TOXICITY
- Conjugated hyperbilirubinemia probably is caused by rifampicin inhibiting the major bile salt exporter pump.
- Asymptomatic elevated bilirubin may also result from dose‐dependent competition with bilirubin for clearance at the sinusoidal membrane or from impeded secretion at the canalicular level.
- Rare hepatocellular injury appears to be a hypersensitivity reaction, and it may be more common with large, intermittent doses.
- Hypersensitivity reactions have been reported in combination with renal dysfunction, hemolytic anemia, or “flu‐like syndrome”.
- PYRAZINAMIDE: METABOLISM
- The half‐life (t1/2) of Pyrazinamide is notably longer than that of either Isoniazid or Rifampicin,
Approximately 10 hours. In patients with pre existing hepatic disease, t1/2 is increased to 15 hours.
- Pyrazinamide, a nicotinic acid derivative, is de‐amidated to pyrazinoic acid in the liver and subsequently metabolized to 5‐hydroxy‐pyrazinoic acid by xanthine oxidase, aldehyde oxidase, and xanthine dehydrogenase.
- In addition, 5‐hydroxy‐Pyrazinamide may be generated during metabolism.
- The kidneys clear metabolites of Pyrazinamide, requiring intermittent dosing in patients
With renal insufficiency.
RIFAMPICIN: MECHANISM OF TOXICITY
- Pyrazinamide may exhibit both dose‐dependent and idiosyncratic hepatotoxicity. Several decades ago, daily doses of Pyrazinamide at 40 to 50 mg/kg commonly caused hepatotoxicity, and a relationship to dose was noted.
- Pyrazinamide alters nicotinamide acetyl dehydrogenase levels in rat liver, which might result in generation of free radical species.
- There may be shared mechanisms of injury for Isoniazid and Pyrazinamide, because there is some similarity in molecular structure.
- Pyrazinamide may induce hypersensitivity reactions with eosinophilia and liver injury or granulomatous hepatitis.
- Many risk factors for ATDH have been reported. The identification of high‐risk patients would be useful to allow early detection of hepatotoxicity and reduce the morbidity and mortality of this condition.
- Variation in risk factor prevalence among different world regions may explain the observed differences in ATDH incidence.
RISK FACTORS: DEMOGRAPHIC
- Advanced age (above 60 years): Older patients may bemore vulnerable to hepatotoxic reactions due to a decreased clearance of drugs metabolized by CYP450 enzymes, and changes in liver blood flow, liver size, drug binding or distribution with aging.
- Female sex : CYP3A activity was higher in females compared with males, which may explain females being more susceptible to ATDH.
- Low body mass index or malnutrition.
Malnutrition results in decreased xenobiotic clearance and higher plasma levels.
RISK FACTORS: HIV/AIDS(1)
- HIV‐infection increases the risk of hepatotoxicity during standard multidrug treatment of activeTB.
- HIV/AIDS patients with acute illnesses have altered activities of oxidative pathways, which may partly explain their increased risk of ATDH.
- Concurrent therapy of TB/HIV co infections requires concomitant use of two to four different antituberculosis drugs and at least three antiretroviral drugs.
- Unfortunately, combined TB/HIV treatment is often complicated by overlapping toxicities and drug–drug interactions
RISK FACTORS: HIV/AIDS (2)
- The majority of the nucleoside reverse transcriptase inhibitors (NRTI) are potentially hepatotoxic (e.g. didanosine and stavudine) and hepatotoxicity has been described for some protease inhibitors (e.g. ritonavir, indinavir and saquinavir).
- The incidence of hepatotoxicity during highly active antiretroviral therapy (HAART) ranges from 2% to18%.
- Drug toxicity, including hepatotoxicity, has been implicated as a major cause of TB or HIV treatment interruption during treatment of TB/HIV co infection. Therefore, HAART is often delayed in HIV‐infected TB patients.
- The concomitant use of antifungals (e.g. fluconazole) which is often seen in HIV‐infected patients, is also a risk factor for ATDH.
RISK FACTORS: Pre‐existent Liver disease
- Hepatitis B and/or C infections are common causes of the chronic liver disease that is frequently seen in populations at risk for TB infection.
- Several studies show that hepatitis B and C co infection increase the risk of ATDH.
- This has also been described for HIV‐positive patients who are being treated with HAART.
- More in general, patients with prior liver disease are at higher risk of hepatotoxicity.
RISK FACTORS: Genetic
- Considerable inter individual variability in metabolism, some of which is caused by human genetic differences.
- Genetic polymorphisms in drug‐metabolizing enzymes can affect enzyme activity. This may cause differences in treatment response or drug toxicity, for example, due to an increased formation of reactive metabolites.
- These polymorphisms may explain differences in incidence of ATDH between different populations.
- The interplay between these genetic risk factors has not been studied.
- Data on genetic risk factors for ATDH are still limited.
RISK FACTORS: Intoxications
- Alcoholism is associated with a higher risk of ATDH because of enzyme induction.
- Patients with alcohol abuse and concomitant use of other hepatotoxic drugs also increases the risk of ATD
RISK FACTORS: Dosing schedules
- Several studies have shown that daily TB treatment in comparison with thrice‐weekly treatment increases the risk of ATDH.
- Although a recent study suggested that dosing schedules in the intensive phase have only little impact on the development of ATDH.
- American Thoracic Society(ATS).
- British Thoracic Society(BTS).
- Task Force of the European Respiratory Society.
- the International Union Against Tuberculosis and Lung Diseases
- Management of ATDH depends on the supposed cause, therefore no unambiguous advice can be given.
- The hepatocellular pattern of liver injury, which is seen in Isoniazid, Rifampicin and Pyrazinamide toxicity, has a predominant initial elevation of alanine aminotransferase (ALT).
- Therefore, this biochemical parameter ismost often used to monitor the liver function during antituberculosis treatment.
- TB should be treated under supervision of a qualified physician.
- Patients should be advised to seek medical care if they experience any signs or symptoms of hepatotoxicity (i.e. jaundice, malaise, nausea and vomiting).
- They should be advised not to drink alcohol during TB treatment.
- During treatment, the liver function only has to be monitored on a regular basis on indication (e.g. in patients with chronic liver disease or increased serum transaminases prior to treatment).
- In the case of signs or symptoms of hepatotoxicity, the liver function should be examined. In the case of confirmed moderate or severe drug‐induced hepatotoxicity, treatment should be interrupted and reintroduced after the hepatotoxicity has resolved.
- In many low‐income countries, where the burden of TB is often high, liver function tests cannot be performed. In those situations one has to rely on clinical symptoms of hepatotoxicity, such as jaundice, abdominal pain, nausea and vomiting.
- The cause of hepatitis during TB treatment can either be the antituberculosis drugs or something else, so the other possibilities have to be excluded before deciding that the hepatitis is drug‐induced
- If moderate or severe ATDH is diagnosed (i.e.serumaminotransferase level >5 times the upper limit of normal [ULN] or >3 times the ULN with symptoms of hepatotoxicity), guidelines recommend to discontinue all drugs until liver function tests become normal.
- When it is not possible to perform liver function tests, it is advisable to wait for an extra 2 weeks after
the jaundice has disappeared before recommencing TB treatment.
- Once the ATDH has resolved, the same drugs are reintroduced consecutively
- Hepatotoxicity is a serious adverse effect and is frequently seen in combined TB/HIV treatment.
- The development of strong pharmacological bases for a more rational use of existing drugs can be very helpful in lowering the risk of adverse effects of TB treatment.
- Studies are needed to demonstrate whether routine transaminase monitoring during TB treatment reduces the incidence or severity of ATDH.
- One of the main future challenges is to design and implement effective and safe treatment regimens for TB/HIV co infected patients.
- Safe systems for treating patients, patient and staff education, appropriate selection of patients for treatment, careful regimen selection, and monitoring help minimize risks.
- The ability to adapt to a changing medical landscape will be crucial to continued safe and effective treatment for TB
Concise up‐to‐date review
- Alma Tostmann et al; Antituberculosis drug‐induced hepatotoxicity:
. Journal of Gastroenterology and Hepatology 23
- Ina Jeong et al;Drug‐induced Hepatotoxicity of Anti‐tuberculosis Drugs and Their Serum Levels .J Korean Med Sci 2015; 30:167‐172.
- Vidyasagar Ramappa, Guruprasad P. Aithal; Hepatotoxicity Related to Anti‐tuberculosis Drugs: Mechanisms and Management .Journal of Clinical and Experimental Hepatology, March 2013, Vol. 3, No.1:37–49.
- Omaima El Bouazzi et al ;First line anti‐tuberculosis induced hepatotoxicity: incidence and risk factors. Pan African Medical Journal. 2016; 25:167.
- Wondwossen Abera et al; Incidence of antituberculosis‐drug‐induced hepatotoxicity and associated risk factors among tuberculosis patients in Dawro Zone, South Ethiopia: A cohort study. International Journal of Mycobacteriology , 5: 14‐20,2016.
- StefanRussmannetal; Current Concepts of Mechanisms in Drug‐Induced Hepatotoxicity. Current Medicinal Chemistry,2009,16,3041‐3053.
- Jussi J. Saukkonen et al; An Official ATS Statement: Hepatotoxicity of AntituberculosisTherapy. Am J Respir Crit Care Med Vol 174. pp 935–952,2006
THANKS FOR YOUR KIND
By Pedmia Shatu Tita