Drug‐Induced Liver Injury: A Mexican View

Short abstract

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Abbreviations

ALF

acute liver failure

ALT

alanine aminotransferase

CTLA‐4

cytotoxic T lymphocyte antigen 4

DILI

drug‐induced liver injury

HILI

herbal‐induced liver injury

LA

Latin America

PD‐1

programmed cell death receptor 1

PDL‐1

programmed cell death receptor ligand 1

TNF

tumor necrosis factor

ULN

upper limit of normal

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Drug‐induced liver injury (DILI) and herbal‐induced liver injury (HILI) are being increasingly recognized throughout the world as important causes of liver damage. The unpredictability of these diseases, together with their low prevalence, underreporting of cases, and the difficulty to establish a precise prognosis, makes DILI and HILI priority topics for Mexican and Latin American (LA) hepatologists.

Main Causes of DILI and HILI

An increase in the global consumption of herbal‐derived supplements (HDS), and with it HDS‐induced DILI, has been observed. ¹ In LA, there is a large market for herbal and HDS because these products are more accessible ² ; most cases are not evaluated at medical appointments and perhaps are mild cases, with just a small percentage being severe cases.

A network established between hepatologists from various LA countries (Latin American DILI Network) described 311 cases of DILI, with 37 of them caused by HDS (10%). Most HILI cases are not reported. ³ , ⁴

The causative agents for DILI in children and in adults vary. Drugs that act on the central nervous system (anticonvulsants) and antimicrobials (minocycline) are the more common causes of DILI in children. Infants are more susceptible to liver injury caused by valproate and are at increased risk for Reye syndrome caused by aspirin. Although propylthiouracil may cause DILI in all age groups, children are more susceptible to severe and fatal hepatotoxicity. ⁶ , ⁷ With increasing age, there is a greater risk for liver injury caused by isoniazid, amoxicillin clavulanate, and nitrofurantoin. ⁸ , ⁹

There is no evidence to suggest that women are at higher risk for all‐cause DILI, but they seem to be at higher risk for liver injury caused by certain medications, such as minocycline, methyldopa, diclofenac, nitrofurantoin, and nevirapine. ¹⁰ DILI is a rare cause of acute liver injury in pregnant women because the use of prescription medications is uncommon. There is no evidence that pregnancy increases the susceptibility to DILI. Common causes of DILI in pregnant women are antihypertensive agents, such as methyldopa and hydralazine, and antimicrobials, including antiretroviral agents. ¹¹

The use of illicit drugs should also be noted because agents such as methylenedioxymethamphetamine have been linked to liver injury and, in some cases, acute liver failure (ALF). ¹² Antibiotics and antiepileptics are the most commonly reported drugs, accounting for 60% of DILIs. ¹³ Tables 1 and 2 list the main agents associated with DILI and HILI.

TABLE 1.

Most Common DILI Agents

Acetaminophen (common drug to cause intrinsic DILI)

Antibiotics

Amoxicillin/clavulanate

Isoniazid

Trimethoprim/sulfamethoxazole

Cephalosporins

Fluoroquinolones

Macrolides

Nitrofurantoin

Erythromycin

Tetracyclines

Minocycline

Antituberculosis agents: isoniazid, rifampicin, pyrazinamide

Antiepileptics

Phenytoin

Carbamazepine

Lamotrigine

Valproate

Analgesics

Nonsteroidal anti‐inflammatory agents

Diclofenac

Immune modulators

Interferon‐beta

Interferon‐alpha

Anti‐TNF agents

Azathioprine

Immune‐checkpoint inhibitors

Ipilimumab (CTLA‐4 inhibitor)

Nivolumab, pembrolizumab, and cemiplimab (PD‐1 inhibitors)

Atezolizumab, avelumab, and durvalumab (PDL‐1 inhibitors)

Cardiovascular drugs

Amiodarone (oral)

Angiotensin‐converting enzyme inhibitors

α‐Methyldopa

Beta‐blockers

Calcium channel blockers

Hydralazine

Hypolipidemics

Fibrates

Niacin

Statins

Miscellaneous

Methotrexate (oral)

Allopurinol

Androgen‐containing steroids

Sulfasalazine

Adapted from Sherlock’s Diseases of the Liver and Biliary System. ²⁵ Copyright 2018, Wiley Blackwell; and American Journal of Gastroenterology. ⁵ Copyright 2021, American College of Gastroenterology.

TABLE 2.

Most Common Herbal and Dietary Supplements in LatinDILI Registry

Anabolic steroids

Herbalife products

Garcinia cambogia

Lipodex

Centella asiatica

Camellia sinensis

Echinacea

Monascus purpureus

Hydroxycut

Ginkgo biloba

Peumus boldus

Chaparral

Adapted from Clinical Liver Disease. ³ Copyright 2020, American Association for the Study of Liver Diseases.

Diagnosis and Prognosis of DILI

DILI has a wide range of clinical presentations, from asymptomatic patients with just low‐grade biochemical alterations to ALF or persistent chronic inflammation. Symptomatic cases show nausea, vomiting, anorexia, upper right quadrant pain on the abdomen, skin rash, pruritus, icterus, ascites, and encephalopathy. ¹⁴

Being an exclusion diagnosis, several tests must be realized to discard other causes of liver injury. A complete medical history should be obtained; a compatible temporal association with the suspected drug can be helpful, and patients should always be asked about the consumption of herbal remedies or products. Severe DILI diagnosis is frequently clinical in a patient with ALF who requires hospitalization.

The diagnostic approach of DILI depends on the biochemical pattern shown at the moment of presentation. r value is defined as the patient’s alanine aminotransferase (ALT)/upper limit of normal (ULN) divided by serum alkaline phosphatase/ULN. An r value >5 suggests hepatocellular injury, while <2 is associated with cholestatic damage, and values between 2 and 5 suggest a mixed damage pattern. ¹⁵

Differential diagnoses include acute viral hepatitis, autoimmune hepatitis, liver ischemia, Budd‐Chiari syndrome, acute biliary obstruction, and Wilson’s disease. Mixed and cholestatic cases of DILI have a small but well‐documented risk for chronicity. ¹⁵ , ¹⁶ Causality has been traditionally established by using scores such as Roussel Uclaf Causality Assessment Method, Maria and Victorino System Clinical Diagnostic Scale, and Drug‐Induced Liver Injury Network expert opinion. ¹⁷ , ¹⁸ Case reports can be helpful in diagnosing atypical or uncommon cases. ¹⁹ , ²⁰

Prognosis is generally determined by the pattern of liver injury, age, comorbidities, Model for End‐Stage Liver Disease score > 19, and Hy’s law (bilirubin levels > 2.5 mg/dL and ALT or aspartate aminotransferase >3 times greater than UNL), which has a good prediction capability for ALF and mortality within 26 weeks. ²¹

A Mexican View

In the last 30 years, HILI has slowly reached an important place as a cause of liver damage in Mexico. In the late 1990s, a study reported that 75% of Mexican medical practitioners had recommended herbal medicines to their patients, and that almost 90% of adults used them regularly as self‐prescription. ²² There are regions of Mexico with high reported use of herbal remedies, such as Oaxaca, Veracruz, Nuevo León, Yucatán, Chiapas, and Hidalgo, which are areas with a large proportion of indigenous inhabitants. The common belief that herbal medicines are harmless and the underregulation of their marketing make them easily accessible. Components of herbs, their side effects, the chemical products used on the crops, the environment, and the clinical host‐related risk factors are the most important determinants of herbal‐related liver damage. ²³ A study conducted by Higuera de la Tijera et al. ²⁴ showed that, in Mexico, liver damage caused by herbology products raises the risk for ALF and death (odds ratio, 8.7 and 35, respectively) compared with cases of DILI related to other drugs. In Mexico, many medications are available “over the counter,” and prescription expeditions are less regulated in comparison with other countries, such as the United States. Besides, herbal supplements are commonly used by the Mexican population, not regulated whatsoever, easily available, and cheap, and our people see these products as “harmless.”

As for DILI, Mexican studies reporting true prevalence are scarce, and most of them are in the form of unpublished abstracts or case reports. A first attempt to create a national register of DILI and HILI cases (Hepa‐tox) was proposed in 2018, but the project did not grow as expected. The Mexican Association of Hepatology is working on the launch of a new platform for a national DILI/HILI register, expected to be open in the months to come. We expect to use a Web‐based system, like Google Forms, to achieve a simultaneous register across the country and to capture useful statistical data prospectively.

Key Points

• There is a great necessity to create a Mexican DILI/HILI database.

• Herbal supplements and remedies, by not being regulated, are a common cause of liver damage in Mexico.

• There is a need for stricter regulation on prescription expenditure among Mexican pharmacies.