Drug-Induced Liver Injury in India — TB Medicines, Herbal Remedies and the RUCAM Assessment

Drug-induced liver injury is liver damage caused by a medicine, herb or supplement. In India, the commonest cause is combination anti-tuberculosis treatment, followed by anti-epileptic drugs and herbal products; in one Indian series of 313 patients, 90-day mortality was 17.3%. Diagnosis requires excluding other causes and scoring causality with RUCAM. — Dr Chetan Kalal, DM Hepatology, Gleneagles Hospital Mumbai

Picture a 34-year-old woman who starts four-drug treatment for pulmonary tuberculosis. Six weeks later she notices dark urine, loses her appetite and turns yellow. Should she stop her TB tablets? Carry on? Wait for the next routine blood test? Each of those choices can go badly wrong, and the right answer depends on how severe the liver injury is.

That scenario is ordinary in Indian hepatology practice. Tuberculosis is common, its treatment is long, and the drugs that cure it are also the drugs most likely to injure the liver. Layer on top of that the widespread use of Ayurvedic preparations, “immunity boosters” and unlabelled supplements, and you have a country where drug-induced liver injury looks very different from the paracetamol-dominated picture described in Western textbooks.

I have seen this from both sides — at the bedside in liver ICUs, and as a co-author of two multicentre studies on the subject: the APASL AARC analysis of drug-induced acute-on-chronic liver failure across Asia, and the Indian nationwide study of Giloy-induced liver injury during COVID-19. This guide explains what DILI is, which medicines cause it in India, how doctors decide a drug is truly to blame, and when to worry.

What drug-induced liver injury actually is

The liver processes almost every medicine we swallow. In most people that happens silently. In a small minority, a drug — or one of its breakdown products — injures liver cells, bile ducts or both.

Doctors separate two kinds. Intrinsic injury is dose-dependent and predictable; paracetamol overdose is the textbook example. Idiosyncratic injury is the more difficult kind: it strikes only a few susceptible people at normal doses, cannot be predicted in advance, and may appear days, weeks or even months after starting the medicine. The EASL Clinical Practice Guidelines describe idiosyncratic DILI as one of the most challenging liver disorders hepatologists face, precisely because there is no single blood test that confirms it.

Blood tests do tell us the pattern of injury, which matters for diagnosis. Hepatologists calculate a ratio (called R) comparing the rise in ALT with the rise in alkaline phosphatase, each expressed as a multiple of the upper limit of normal. A high ratio means hepatocellular injury, where liver cells themselves are damaged; a low ratio means cholestatic injury, where bile flow is disrupted; values in between are called mixed.

Why does the pattern matter so much? Because hepatocellular injury accompanied by jaundice is the dangerous combination. The ACG clinical guideline notes that DILI carries a mortality of up to 10% when hepatocellular jaundice is present — and patients with progressive jaundice, with or without clotting abnormalities, should be referred to a tertiary liver centre.

The Indian picture: TB drugs, anti-epileptics and herbal products

The best long-term Indian data come from St John’s Medical College, Bangalore. In a series of 313 consecutive DILI patients studied over eleven years, the leading cause by a wide margin was the four-drug anti-tuberculosis combination (58%), followed by anti-epileptic drugs (11%), olanzapine (5.4%) and dapsone (5.4%). Overall 90-day mortality was 17.3% — and notably higher for anti-TB drug hepatitis (21.5%) than for other drugs (11.4%).

A follow-up analysis of 269 patients with anti-TB drug liver injury from the same centre is even more sobering. Seventy-one per cent developed jaundice. A quarter (25.7%) progressed to acute liver failure. Three-quarters of cases arose within the first two months of treatment, and the 90-day mortality was 22.7%. When encephalopathy (confusion from liver failure) developed, mortality rose to 69.6%.

The Indian National Association for the Study of the Liver (INASL) consensus on acute liver failure puts it plainly: in India, viral hepatitis is the commonest cause of acute liver failure, and anti-tuberculosis drug hepatitis is the second.

Then there are herbal and complementary medicines. The APASL DILI consensus guideline — written with an explicit Asian focus — singles out two problems as the reason DILI is probably more common in Asia than elsewhere: tuberculosis treatment, and the ubiquitous use of traditional and complementary medicines. These products are often perceived as “natural and therefore safe”. They are neither regulated like drugs nor tested like drugs, and their contents are frequently unknown even to the person taking them.

When DILI strikes a liver that is already damaged

This is the part of the story most patient websites miss, and it is the part I consider most important.

A drug reaction in someone with a healthy liver is usually survivable once the drug is stopped. The same reaction in someone with undiagnosed fatty liver disease, alcohol-related liver disease or silent cirrhosis can tip them into acute-on-chronic liver failure (ACLF) — a syndrome where a sudden insult on top of chronic liver disease causes rapid failure of the liver and often other organs.

In the APASL ACLF Research Consortium (AARC) database, which I contributed to, drugs were identified as the trigger in 329 of 3,132 ACLF patients — 10.5%. Complementary and alternative medicines were responsible in 71.7% of those, and combination anti-TB therapy in 27.3%. The underlying liver disease was commonly alcohol-related (28.6%), cryptogenic (25.5%) or NASH (16.7%) — in other words, many of these patients may not have known their liver was already vulnerable. Every one of them was jaundiced; 88% had ascites and 46.5% had encephalopathy. Ninety-day mortality was 46.5%, significantly higher than the 38.8% seen in ACLF from other causes.

The practical lesson is uncomfortable but simple. If you have any chronic liver condition — including fatty liver found incidentally on an ultrasound — the threshold for taking an unprescribed herbal product should be very high, and any new prescription deserves a conversation with your doctor about your liver.

Herbal liver injury: what the Giloy outbreak taught us

During the COVID-19 pandemic, Giloy (Tinospora cordifolia) was widely promoted in India as an immune booster. Hepatologists across the country began seeing patients with unexplained hepatitis who shared one detail in their history.

We pooled those cases in a multicentre study spanning 13 centres in nine locations, published in Hepatology Communications in 2022. Forty-three patients were included, more than half of them women. The median interval from first taking Giloy to developing symptoms was 46 days — long enough that most patients never connected the two. Causality assessment rated the injury as probable in 67.4%. Presentations ranged from acute hepatitis to acute liver failure, but the commonest was acute worsening of a chronic liver disease the patient often did not know they had.

Two findings stood out. The antinuclear antibody (ANA) was frequently positive, and liver biopsies showed injury with autoimmune features. Our conclusion was that Giloy can cause acute hepatitis with autoimmune features and can unmask silent autoimmune hepatitis. The outbreak deserves its own telling; the broader point is that a herb’s popularity says nothing about its safety.

When I take a history in clinic, I ask about “any powders, kadhas, tablets, capsules or tonics” rather than “any medicines”. Patients rarely think of these as drugs. They should.

How doctors confirm DILI — and why RUCAM matters

No blood test proves drug-induced liver injury. The diagnosis is built by exclusion and by weighing probabilities, which is why an experienced hepatologist’s assessment matters.

First, other causes must be ruled out. That means testing for hepatitis A, B, C and E, autoimmune hepatitis, Wilson disease in younger patients, biliary obstruction on imaging, alcohol, and ischaemic injury. In India, hepatitis B deserves special mention: reactivation of hepatitis B during TB treatment or chemotherapy can mimic DILI exactly, and the management is completely different.

Second, the likelihood that a specific drug is responsible is scored. The standard tool is RUCAM — the Roussel Uclaf Causality Assessment Method — updated by Danan and Teschke in 2015. It awards points for the timing between starting the drug and the injury, the course after stopping it, risk factors, concomitant drugs, exclusion of alternative causes, previously known hepatotoxicity of the drug, and response to re-exposure. The total places each suspect drug in a category from “excluded” to “highly probable”. RUCAM is especially useful when a patient is taking several medicines at once — which, in anti-TB DILI, is almost always the case.

Third, severity is assessed: bilirubin, INR, the presence of encephalopathy or ascites, and kidney function. Both the Indian anti-TB series and the AARC ACLF data found that these markers, rather than the height of the liver enzymes alone, predicted who would die. A very high ALT with normal bilirubin and INR is usually less dangerous than a moderate ALT with rising jaundice and a lengthening INR.

Occasionally a liver biopsy is needed — typically when autoimmune hepatitis cannot be distinguished from DILI, since the treatment decisions differ.

Treatment, re-starting TB drugs and when to go to hospital

The single most effective treatment is withdrawing the offending drug early. For most patients with mild injury, that is enough, and the liver recovers over weeks.

Tuberculosis creates a genuine dilemma, because stopping TB treatment carries its own serious risk. Decisions about which drugs to pause, whether to use a liver-sparing interim regimen, and how to reintroduce the drugs one by one belong with the treating physician and a hepatologist working together. The APASL consensus devotes specific guidance to anti-TB DILI for exactly this reason. Please do not stop, reduce or restart TB medicines on your own.

Corticosteroids are not routine. The ACG guideline describes their role as controversial, reserving them for cases where DILI cannot be distinguished from autoimmune hepatitis or where autoimmune features are prominent — a situation the Giloy cases illustrate well.

If DILI progresses to liver failure, care moves to a liver ICU with transplant capability. Some patients recover with intensive support; others need specialist evaluation for liver transplantation. Early referral matters because the window for transplant can close quickly.

Seek urgent medical care if, while taking any medicine or supplement, you develop: yellow eyes or skin; dark, tea-coloured urine; persistent vomiting or inability to eat; confusion, excessive sleepiness or behaviour change; abdominal swelling; or easy bruising or bleeding. These are signs that the liver injury may be serious.

Most drugs do not harm most livers. But for the patient on TB treatment who turns yellow, or the person with fatty liver who has been taking an unlabelled herbal tonic for two months, recognising drug-induced liver injury early is the difference between a few difficult weeks and a liver transplant assessment. This information is educational — please consult your physician before making any change to your treatment.

Frequently asked questions

Which TB medicines can damage the liver?

Three of the four first-line anti-TB drugs — isoniazid, rifampicin and pyrazinamide — are known to cause liver injury. Because they are given together, doctors usually cannot tell from symptoms alone which one is responsible. In Indian data, about three-quarters of cases occur in the first two months of treatment. Never stop TB drugs without your doctor’s advice.

Are Ayurvedic and herbal medicines safe for the liver?

Not automatically. In the APASL AARC study of drug-induced acute-on-chronic liver failure across Asia, complementary and alternative medicines were the commonest trigger (71.7%). An Indian multicentre study linked Giloy to liver injury with autoimmune features in 43 patients. Tell your doctor about every herbal product you take.

How is drug-induced liver injury diagnosed?

There is no single confirmatory test. Doctors exclude viral hepatitis, autoimmune hepatitis, alcohol, bile duct blockage and other causes, then use the RUCAM causality scale to judge how likely it is that a particular drug is responsible. Severity is judged mainly by bilirubin, INR and signs of liver failure.

Will my liver recover after stopping the drug?

Most people with mild DILI recover once the culprit drug is stopped. The outlook is worse when jaundice, confusion or ascites develop, and much worse if the injury occurs on top of existing liver disease — drug-induced ACLF had a 90-day mortality of 46.5% in the AARC cohort.

Can I take TB treatment again after liver injury?

Often yes, but only under close supervision. Doctors may use a modified regimen or reintroduce drugs one at a time while monitoring liver tests. This decision should be made jointly by your TB physician and a hepatologist.

I have fatty liver. Should I be more careful with medicines?

Yes. Underlying liver disease, including fatty liver, was common among Asian patients whose liver failed after a drug insult. Avoid unprescribed supplements and herbal tonics, and tell every prescribing doctor about your liver condition.

Author: Dr Chetan Kalal — DM Hepatologist, Gleneagles Hospital Mumbai. ORCID: https://orcid.org/0000-0002-5284-7890

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