Hepatitis

General approach

Patients presenting with right upper quadrant discomfort and jaundice should be triaged promptly using ultrasound into those with surgically correctable causes, and the rest. Finding a rise in canalicular enzymes with an ‘obstructive’ bilirubin pattern (raised conjugated as well as unconjugated bilirubin levels) does not automatically imply that this is a surgical condition, because this pattern may also be seen in the later stages of acute viral hepatitis and with some medication-induced hepatitic illnesses. If the ultrasound is unhelpful, consider medication, alcohol, and viral infections as the most likely causes, although a small proportion may be due to auto-immune hepatitis. Ischaemic injury following a major hypotensive episode is usually self-evident, but can present with dramatically high enzyme levels

• Take a medication history. Take it again the next day, ideally with assistance from a relative. Practically any medication should be viewed with suspicion, and stopped until there is greater clarity.
• Take an alcohol history. Take an alcohol history from a relative.
• Examination should include actively looking for features of encephalopathy – get the patient to draw a house or a star (whichever you are better at providing for copying) as well as attempting to elicit a flap, which is a relatively late sign. One of the earliest features is a disturbance of sleep cycle, with nocturnal wakening or restlessness.
• Before ascribing all jaundice to the liver itself, consider haemolytic causes, particularly if the patient is anaemic. In patients with cirrhosis and portal hypertension, GIT bleeding from varices may contribute to worsening jaundice, or even new onset jaundice, as well as being associated with a creatinine rise from the extra intestinal protein load.
• Investigations should include tests of liver function (INR and albumin) as well as liver damage (enzymes.) Don’t forget to check urea and electrolytes as patients may be significantly hyponatraemic or in renal failure. Check hepatitis A as well as hepatitis B status; C is rare but may also be worth considering.
• In a confused or unconscious patient, check the blood glucose as a matter of urgency, and in most very ill hepatitis patients, regular monitoring of glucose is warranted.

Other complications to look out for and manage actively include hyponatraemia, sepsis, particularly with gram negative coliforms, bleeding (treat acute episodes with 10 ml/kg of FFP, and packed cells as required; (most authorities recommend prophylactic parenteral vitamin K although evidence of efficacy is tenuous), renal impairment (drugs, dehydration, sepsis) and encephalopathy. (See individual items for more detail.)

Drug induced liver injury

Medication induced liver injury is usually associated with AST and ALT rises. Consider:

• Acute toxicity – e.g. paracetamol overdose
• Jaundice without liver damage – e.g. the rifampicin associated organic anion transporter issue present in some patients on TB therapy who are well and have hyperbilirubinaemia without ALT rises
• Canalicular enzyme rises – these are rare but well described – e.g. that caused by the immune-mediated vanishing bile duct syndrome associated with a number of medications, notably co-amoxyclav.
• The better recognised DILIs associated with elevated ALt, and due to a large number of potential culprit drugs.

Definitions of DILI vary between groups; the key point is when to stop treatment, and most would agree that cessation is appropriate if:¹

• the ALT is >5 times upper limit of normal in an asymptomatic patient,
• or if the patient is jaundiced,
• or has gastrointestinal symptoms suggestive of liver disease and an ALT > 3 times ULN.

Some of the more common drugs associated with acute hepatitis are the anti-epileptics (phenytoin and carbamazepine), the anti-tuberculous drugs, sulphonylureas, nevirapine and efavirenz, and co-trimoxazole. Drugs taken by a patient for a long time can still cause hepatitis. The two common scenarios are patients on TB treatment, ARVs or both, and patients on anti-epileptics. If on anti-epileptics, stop all of them and manage seizures using benzodiapines in the short term. Ask for advice about introducing anti-epileptics again, as cross-sensitivity between agents is well described. Patients are often on multiple drugs, and outcomes in those admitted with moderate or severe DILI are still poor, with mortality in this group above 40%²

Management if TB/ARV associated DILI:

• Stop ALL medication if in doubt. This can be nuanced using probabilities – for instance if a patient stable on an ARV regimen containing agents unlikely to cause hepatitis (e.g. dolutegravir/tenofovir/lamivudine) and TB medication was introduced recently, then it is more likely to be the latter.
• If the patient clearly needs TB treatment (severe tuberculosis, very immunocompromised), introduce a holding regimen of agents very unlikely to cause hepatitis. Traditionally this was amikacin, ethambutol and levofloxacin, but an alternative if available may include medications usually reserved for drug resistant tuberculosis such as linezolid, bedaqualine and levofloxacin (discuss with a specialist).
• When ALT is <100 and bilirubin has normalized:
• Add rifampicin in full dose, and check bilirubin and ALT after 3 days of treatment.
• If no enzyme rise, on day 4 add isoniazid in full dose
• Check ALT again after 3 days on rifampicin and INH.
• If no enzyme rise after another three days, consider a pyrazinamide challenge if TB meningitis or INH or rifampicin resistance documented.
• Continue to monitor ALT twice per week for the next three weeks, and then fortnightly for a further month and then monthly for a further 3 months. This is important: the problem isn’t necessarily over simply because nothing happened during the relatively short time that the patient was in the ward!

Treatment duration using adjusted combinations of TB medication:

This depends on whether the DILI developed during the intensive or continuation phase.

Medication left out	Started in intensive phase	Started in continuation phase
PZA	INF Rif and ethambutol for 9 months
Rifampicin	Amikacin for 2/12; PZA, levoflox, INH and ethambutol for 18 months	Levoflox, INH, ethambutol for 18 months
Isoniazid	Levoflox, rifampicin, ethambutol and PZA for 6 months	Levoxifloxacin, rifampicin and ethambutol for 6 months

What to do about anti-retrovirals

Patients developing hepatitis on both anti-tuberculous medication and anti-retrovirals pose a particular problem, and in patients with intercurrent hepatitis B, stopping lamivudine (and/or tenofovir) may cause the hepatitis to flare. Nevirapine tail-off after discontinuation also exposes the individual’s HIV to subtherapeutic levels, leading to the theoretical possibility of clinically important drug resistance.

Evidence-based management recommendations are sparse, but consider continuing with tenofovir and lamivudine, and substituting the nevirapine/efavirenz with lopinavir/ritonavir. In severely symptomatic vomiting patients this may not be practicable and complete cessation of all oral medication may be necessary.

Perspective – introduction of anti-tuberculous medication

A randomised controlled trial of 175 HIV negative non-alcoholic patients from India³ compared the re-introduction of medication with escalating dose INH first followed by escalating dose rifampicin (British Thoracic Society recommendation), full dose rifampicin first and full dose INH after a week (American Thoracic Society recommendation), or simply re-starting patients on rifampicin, INH, and PZA in full doses all at once. Recurrent hepatitis was found in 19 (11%) of patients overall, and although the between-group differences were not statistically significant, the trial was underpowered to conclude that there is no difference between the three re-introduction regimens.

Hepatitis B.

Needlestick and other route HBV exposure in healthcare workers

Determine vaccination status if known. If vaccinated previously and has responded with satisfactory antibody rise (HBsAb > 10 mIU/ml) of if have this antibody level after childhood infection then it is reasonable to regard the individual as protected. If antibody level unknown or <10 mIU/ml, then give stat dose of HB immunoglobulin (0.06ml/kg) and repeat after one month. At the same time give a dose of HBV vaccine, and further doses at 1, 2, and 12 months.

Hepatitis B infection

Diagnosis.

The easy one is acute hepatitis B – the patient is generally ill with jaundice and markedly raised ALT. The HBsAg and HBeAg are positive, the anti-HBcIgM is positive, but other antibodies (HBeAb and HBsAb) are negative. If measured (and it is unnecessary to do so), the HBV DNA levels would be very high. During recovery, the ALT normalises, HBsAg is cleared and further antibodies appear (HBsAb, HBeAb, HBcAb.)

The problem arises with alternative infection statuses. A common one, which may last for many years, is the immune tolerant state with normal ALT, relatively high viral loads (e.g. HBV DNA > 20 000) and positive HBsAg and HBeAg. This may resolve by so-called immune clearance phase with dropping viral loads and antigen levels, and transition to the recovered state with antibodies and no antigen. If the HBsAg remains positive and the ALT is elevated for 3 to 6 months, then this is labelled chronic hepatitis B, and it may be either HBeAg positive, with relatively high viral loads, or HBeAg negative with lower loads.⁴

Clearly this approach in HIV depends on a CD4 threshold. With a treat all strategy, the only issue is whether one recognizes the (rare) possibilities of HepB related harm on ARVs.

A more nuanced approach incorporating HBeAg and HBV DNA is recommended for HIV negative individuals. In this approach, those with elevated ALT are still considered for liver biopsy, with treatment decisions incorporating biopsy information, HBV DNA levels and HBeAg status. The main difference is that ALT follow up intervals are 3-6 months for those with higher viral load, and 6-12 months with lower loads, with HBV DNA levels also being done at follow up in the latter. The cutpoint for low and high viral loads is 20 000 if HBeAg positive and 2000 if HBeAg negative.

Treatment

Treatment option are either pegylated interferon (extremely expensive) or combination tenofovir/lamivudine (or emtricitabine in place of lamivudine.) If used in HIV, these two obviously need to be accompanied by a third agent, and dolutegravir is fine. If the ARV regimen has to be adjusted because of HIV related issues, try to continue both TDF and 3TC, as stopping them may lead to a hepatitis B flare.⁵ When used as monotherapy, resistance to lamivudine develops in 70% of patients at four years.

In HIV negative patients, lamivudine can be dosed at 150mg daily, but tenofovir remains at 300mg daily. Both agents will need dose adjustment if there is associated renal impairment. When considering these agents in acute liver failure, it may be reasonable to use lamivudine monotherapy (as resistance is less likely to develop with short courses) where tenofovir is relatively contra-indicated because of renal impairment.

It needs to be remembered that while treatment has impressive effects on viral clearance, efficacy is more modest on longer-term endpoints, with reported HBeAg loss at one and five years being 21% and 49% respectively, and HBsAg seroconversion 3% and 11%; more than 85% are expected to show some improvement in histology after 5 years. Benefit in terms of mortality, progression to cirrhosis, and development of hepatocellular carcinoma is very feasible, but as yet unproven.⁶

Besides chronic hepatitis B, other indications for treatment are Hepatitis B causing acute liver failure, patients with hepatitis B associated decompensated cirrhosis (ascites, variceal bleeds, or encephalopathy) or cirrhosis with detectable HBV DNA, and patients receiving immunosuppressive treatment such as rituximab.

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1. Abbara, A., Chitty, S., Roe, J.K. et al. Drug-induced liver injury from antituberculous treatment: a retrospective study from a large TB centre in the UK. BMC Infect Dis 2017; 17, 231 . https://doi.org/10.1186/s12879-017-2330-z ↩

2. MEHTA, R et al. Treatment outcomes among patients admitted to hospital with antiretroviral and/or antituberculosis drug-induced liver injury. South African Medical Journal, [S.l.], v. 111, n. 5, p. 474-481, apr. 2021. ISSN 2078-5135. doi:10.7196/SAMJ.2021.v111i5.15353. ↩

3. Sharma SK, Singla R, Sarda P, et al. Safety of three different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. Clinical Infectious Diseases. 2010;50:833-9 ↩

4. Spearman CW, Sonderup MW, Botha JF et al. South African guideline for the management of chronic hepatitis B: 2013, S Afr Med J 2013;103(5):335-349. DOI:10.7196/SAMJ.6452 ↩

5. Mendelson et al. South African HIV Clinicians Society. Management of HIV-Hepatitis B coinfection. S African J HIV Med 2011;(Apr):27-33 ↩

6. Coffin CS, Fung SK, Ma MM. Management of chronic hepatitis B: Canadian Association for the study of the Liver consensus guidelines. Can J Gastroenterol 2012;26(12):917-938 ↩

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