Case of the Month

October 2015

Title: A Little Liver and a Big TB problem
David P Moore - Department of Paediatrics and Child Health, Chris Hani Baragwanath Academic Hospital and University of the Witwatersrand david.moore@wits.ac.za 

A 6-week old female infant, newly diagnosed with HIV, was started on appropriate doses of anti-tuberculosis treatment on day five of her sentinel hospital admission with pneumonia, in view of poor weight gain (severe acute malnutrition: weight 3.1 kg (weight-for-age Z-score: -3.29 SD), a ‘suggestive chest X-ray’ and splenic microabscesses visualised on the abdominal ultrasound (Figure 1).

Figure 1: Abdominal ultrasound from first hospital admission

Ultrasound of the spleen demonstrates a diffuse coarse echogenicity with multiple hypoechoic lesions highly suggestive of microabscesses. The radiologic differential for microabscesses in the spleen includes disseminated TB, non-tuberculous mycobacterial infection (Mycobacterium avium complex), and fungal infections.

Her CD4 count was 53 cells/mm3 (2.02%). The baseline viral load was 4,170,560 RNA copies/mL. There was no known TB contact.

She was treated for community-acquired pneumonia, and responded well to therapy. She was discharged four days later in good health, with a plan to initiate her onto antiretroviral therapy (ART) in 4 weeks, once stabilised on anti-TB treatment.

Question 1: According to the World Health Organization, what clinical stage of HIV does this child fall into?

Question 2: What investigations can be sent to confirm a microbiological diagnosis of tuberculosis in this infant?

Question 3: What anti-tuberculosis regimen would you use in such a child?

Question 4: What doses of first-line anti-tuberculosis drugs are recommended for children, according to the South African TB Guidelines?

Question 5: What additional medication is warranted in such a child, and why?

Answer Q1: WHO Stage IV in view of the severe failure-to-thrive [1].

Answer Q2:
  • Gastric aspirates for TB GeneXpert, TB culture and TB susceptibility testing;
  • Induced sputum for TB GeneXpert, TB culture and TB susceptibility testing;
  • TB blood culture if chest X-ray is suggestive of miliary tuberculosis.

Answer Q3: It is recommended that HIV-infected children with severe immunosuppression be treated with four-drug anti-tuberculosis therapy (Regimen 3B). Isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) is the regimen of choice. Children with suspected miliary tuberculosis or TB meningitis are frequently started on ethionamide (Eo) rather than ethambutol as it has better CSF penetration [2].

Answer Q4:
  • H: 10-15 mg/kg/day (maximum daily dose 300 mg);
  • R: 10-20 mg/kg/day (maximum daily dose 600 mg);
  • Z: 30-40 mg/kg/day (maximum daily dose 2.0 g);
  • E: 15-25 mg/kg/day (maximum daily dose 1.2 g) [2].

Answer Q5:
  • Pyridoxine (vitamin B6) to prevent against isoniazid-induced neuropathy in view of the child’s nutritional status;
  • Co-trimoxazole prophylaxis, for prevention of Pneumocystis jiroveci pneumonia [3].
Case continued

On review at the paediatric ART clinic one month later, it was noted that she was pyrexial but otherwise stable, and that she had not gained weight since her previous admission (weight 3.09 kg: weight-for-age Z-score: -4.24 SD). She was admitted for further evaluation. The admitting clinicians conducted a septic work-up on the child, and collected blood for ‘liver function test’ analysis, although she was not clinically jaundiced. A chest X-ray was repeated (Figure 2).

Figure 2: Chest X-ray from second hospital admission

Frontal chest X-ray demonstrates reticular pattern in the right middle zone, with some obscuration of the right heart border. The child is rotated in this X-ray, but there are no obvious features to suggest hilar adenopathy, i.e. no lobulated, dense masses filling the hilar points

Question 6: Why would a liver function test be warranted in this infant, despite the fact that she was not clinically jaundiced?

Answer 6: The first-line anti-tuberculosis agents (isoniazid, rifampicin and pyrazinamide) are known to be hepatotoxic. Furthermore, baseline transaminase levels are recommended before initiating infants onto antiretroviral therapy (ART) if they are on concomitant anti-TB treatment in view of the potential hepatotoxic effects of antiretroviral agents [3].

Case continued
The child’s alanine transaminase (ALT) and aspartate transaminase (AST) levels were 266 and 464 U/L, respectively, i.e. 8.9× and 5.9× the upper limit of normal (normal ranges: ALT, 3-30 U/L; AST, 0-79 U/L).

A liver sonar was repeated (Figure 3).
Figure 3: Abdominal Ultrasound from second hospital admission
Right lobe of the liver 
Gall bladder 

Portal vein

Hepatic vein


In the repeat ultrasound, the liver appears homogenous with no focal areas of increased or decreased echogenicity. There are no obvious calcifications. There is normal colour flow on Doppler ultrasound of the portal and hepatic veins. Resistive index to flow in these vessels was not calculated. The splenic microabscesses are less prominent.

Question 7: Are these transaminase levels a cause for concern, and if so what differential diagnosis would you consider as a cause for this clinical picture?

Answer 7: Yes: transaminase levels above five times the upper limit of normal warrant withdrawal of potentially hepatotoxic drugs [2, 4]. In children with clinical evidence of hepatitis (e.g. jaundice, vomiting, right upper quadrant pain), transaminase levels above three times the upper limit of normal warrant withdrawal of potentially hepatotoxic medications.

Differential diagnosis:
  • TB drug related liver injury;
  • Co-trimoxazole hepatotoxicity;
  • Viral hepatitis, including hepatitis A, B, C, cytomegalovirus (CMV), HIV;
  • Hepatitis secondary to bacterial sepsis;
  • Hepatitis caused by tuberculosis;
  • Hepatitis caused by congenital infections, e.g. syphilis.
Case continued

It was decided to discontinue her anti-tuberculosis treatment, in view of the transaminase elevations. ‘Liver friendly’ anti-TB treatment (amikacin, ciprofloxacin – subsequently changed to moxifloxacin – and ethambutol) was continued.

Results of the child’s baseline TB work-up were as follows:
  • Gastric aspirate GeneXpert negative for Mycobacterium tuberculosis DNA;
  • Two gastric aspirates smear negative for acid-alcohol fast bacilli (AFB) and culture negative for M. tuberculosis.

A work-up for viral hepatitis we conducted, and serology for hepatitis A, B and C were negative. Human cytomegalovirus (CMV) viral load was lower than the detectable limit. Syphilis serology was negative.

ALT and AST were repeated after seven days of discontinuation of the first-line TB regimen: the ALT level was 84 U/L, and ALT was 94 U/L (2.8× and 1.2× the upper limit of normal, respectively). The child’s clinical condition had improved considerably and, as at admission, there were no clinical features of hepatitis.

Question 8: What management option would you adopt at this stage in the child’s clinical course?
Answer Q8: There is scope to consider a step-wise re-challenge with first line anti-tuberculosis agents at this stage [4]. It would also be useful to repeat the microbiologic work-up for TB, in order to confirm there is a strong basis for continuing the anti-TB treatment.

Case continued
The clinicians opted to re-challenge with isoniazid (dosed at 9 mg/kg/day), and continued the amikacin, ciprofloxacin and ethambutol.

A TB blood culture was collected: it flagged positive after two days of incubation, but was contaminated, although AFBs were visualised on microscopy. Antigen testing (MPT64) confirmed the presence of M. tuberculosis complex on the TB blood culture.

ALT and AST were repeated six days after isoniazid re-challenge. ALT was now 180 U/L (6.0× upper limit of normal) and AST was 483 U/L (6.1× upper limit of normal) (see Figure 4).

ACE: amikacin, ciprofloxacin, ethambutolAST: aspartate transaminase
ACE + H: amikacin, ciprofloxacin, ethambutol and isoniazidRHZE: rifampicin, isoniazid, pyrazinamide and ethambutol
ALT: alanine transaminase

Question 9: What is the likely diagnosis, and what should be done at this stage?

Answer Q9:
This is likely a case of isoniazid-induced liver injury, in view of the rapid deterioration in liver function tests soon after re-challenge with the drug. Isoniazid should be withdrawn at this juncture, and ‘liver friendly treatment’ continued, pending resolution of the hepatitis.

An adverse reaction to pharmaceutical therapy form may be admitted in such a case, and a medic-alert bracelet issued to the child to alert clinicians caring for the child in future about the child’s previous reaction to isoniazid.

Case continued

Isoniazid was withdrawn from the child’s treatment regimen, and liver functions were repeated intermittently over the course of the ensuing days and weeks. Antiretroviral therapy was initiated 74 days after the initial positive HIV PCR result. The first-line anti-TB drugs rifampicin (low dose (5.3 mg/kg/day) followed by higher dose (10.3 mg/kg/day) once liver functions were confirmed to be stable on this drug) and pyrazinamide were subsequently re-started.

The liver function tests remained stable on the final treatment regimen: moxifloxacin, ethambutol, rifampicin and pyrazinamide (see Figure 5).

3TC: lamivudineAME +R: amikacin, moxifloxacin, ethambutol and higher-dose rifampicin
ABC: abacavirART: antiretroviral therapy
ACE: amikacin, ciprofloxacin, ethambutolAST: aspartate transaminase
ACE + H: amikacin, ciprofloxacin, ethambutol and isoniazidLPV/r: lopinavir and ritonavir
ALT: alanine transaminaseMERZ: moxifloxacin, ethambutol, rifampicin and pyrazinamide
AME: amikacin, moxifloxacin, ethambutolRHZE: rifampicin, isoniazid, pyrazinamide and ethambutol
AME +r: amikacin, moxifloxacin, ethambutol and low-dose rifampicin

The child has remained well on her current anti-TB regimen and ART. At follow-up, she has exhibited an excellent immunologic and virologic response (CD4 2,198 (39.97%) and viral load 415 RNA copies/mL) at seven months on ART.

A repeat TB blood culture was negative.

Question 10: What duration of anti-TB treatment should be given to this child, and why?

Answer Q10:
Duration of TB treatment in this child is contentious, as she is on a ‘novel regimen’ which excludes isoniazid. Close clinical follow-up, with monitoring of the growth pattern, and active exclusion of TB by submission of appropriate specimens if clinical status deteriorates, will guide management decisions.

The management team caring for this child has elected to give her a minimum of 12 months of anti-TB treatment.


Toxicity to first-line anti-TB drugs is uncommon in clinical paediatrics, however it may be devastating if not managed appropriately [5]. Although isoniazid, rifampicin and pyrazinamide all have the potential for causing hepatocyte damage, isoniazid is the most frequently implicated agent [6]. Isoniazid is metabolised by N-acetyltransferase in the liver, and young children tend to metabolise the drug more efficiently than do older children and adults [7]. Recommended doses of isoniazid in the South African Paediatric TB Guidelines (10-15 mg/kg/day) and revised World Health Organization (WHO) Guidelines (10 mg/kg/day) is higher than those previously recommended in paediatric treatment guidance documents ( ̴5 mg/kg/day) [8].

It is expedient to do baseline liver function tests (ALT, AST) in young HIV-infected children who are on anti-TB treatment, in whom we are soon to initiate ART [9]. No baseline liver functions were done in the child reported here, and the hepatitic picture would have been missed entirely if the test was not conducted at the second hospital admission.

A positive TB blood culture in this child is reassuring of the fact that continuation of anti-TB therapy is warranted in this child. Duration of anti-TB therapy is debatable, but as isoniazid cannot be used with safety, at least 12 months of treatment is justified.


Thank-you to Dr Pedro da Silva (Braamfontein TB Laboratory) for assistance in interpreting the TB blood culture result), and Dr Nasreen Mahomed (Respiratory & Meningeal Pathogens Research Unit, ) for expertise in interpreting the radiological investigations done in this case. Ethics permissions for online publication of this case were obtained from the Chris Hani Baragwanath Medical Advisory Committee and the University of the Witwatersrand Human Research Ethics Committee (Medical)


  1. World Health Organization, Antiretroviral therapy for HIV infection in infants and children: towards universal access, ed. World Health Organization2010, Geneva: World Health Organization.
  2. South African National Department of Health, Guidelines for the Management of Tuberculosis in Children, South African National Department of Health, Editor 2013, South African National Department of Health: Pretoria.
  3. South African Department of Health, National consolidated guidelines for the prevention of mother-to-child transmission of HIV (PMTCT) and the management of HIV in children, adolescents and adults, South African Department of Health, Editor 2014, South African Department of Health: Pretoria.
  4. Moore, D.P., et al., Childhood tuberculosis guidelines of the Southern African Society for Paediatric Infectious Diseases. South Afr J Epidemiol Infect, 2009. 24(3): p. 57-68.
  5. Wu, S.S., et al., Isoniazid-related hepatic failure in children: a survey of liver transplantation centers. Transplantation, 2007. 84(2): p. 173-9.
  6. Donald, P.R., Antituberculosis drug-induced hepatotoxicity in children. Pediatr Rep, 2011. 3(2): p. e16.
  7. Schaaf, H.S., et al., Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Archives of disease in childhood, 2005. 90(6): p. 614-8.
  8. Thee, S., et al., Pharmacokinetics of isoniazid, rifampin, and pyrazinamide in children younger than two years of age with tuberculosis: evidence for implementation of revised World Health Organization recommendations. Antimicrob Agents Chemother, 2011. 55(12): p. 5560-7.
  9. South African National Department of Health, The South African Antiretroviral Treatment Guidelines, 2013, South African National Department of Health, Editor 2013, South African National Department of Health: Pretoria.

Earn CPD Points


FIDSSA Members can earn CPD points by logging into the secure section of the website and visiting the MyCPD section.