Hepatotoxicity Associated with Labetalol Use: A Case Report with Systematic Review and Disproportionality Analysis Using FAERS

Abstract

Labetalol is widely prescribed as a first‐line antihypertensive in pregnancy; however, rare but potentially severe idiosyncratic hepatotoxicity has been reported, with a disproportionately strong reporting signal for liver injury relative to other β‐blockers. In this report, a fatal case is described in which mild initial symptoms rapidly progressed to fulminant hepatocellular injury and acute liver failure within days, underscoring the importance of early recognition of drug‐induced liver injury and prompt discontinuation of labetalol. A PRISMA‐guided systematic review of MEDLINE, Embase, CINAHL, Cochrane Library, PubMed, and Google Scholar (from inception to December 2025) identified 27 published case reports. Patients were predominantly female (≈80%), and one‐third were pregnant or postpartum. Latency ranged from 7 to 365 days (median ≈60 days). The injury phenotype was consistently hepatocellular, often with autoimmune‐like serologic or histologic features. Outcomes included full recovery in most (≈75%), but also liver transplantation and death. In the FDA Adverse Event Reporting System (2020Q1‐2025Q1), labetalol showed strong disproportionality signals for DILI (PRR 22.7, 95% CI 15.6‐33.1; ROR 23.7, 95% CI 16.0‐35.1; IC025 2.5) and autoimmune hepatitis (PRR 59.8, 95% CI 34.1‐104.8; ROR 60.9, 95% CI 34.4‐108.1; IC025 2.8), which persisted when restricted to other β‐blockers as comparators. Signals for acute hepatic failure and hyperbilirubinemia were elevated but less statistically robust. The available evidence is consistent with a clinically meaningful and biologically plausible association between labetalol and idiosyncratic hepatotoxicity, supporting heightened clinical awareness and further mechanistic and population‐based study.

Introduction

Labetalol is a combined α‐ and β‐adrenoceptor antagonist widely used for chronic and pregnancy‐associated hypertension, where it is commonly recommended as first‐line therapy. ¹ , ² , ³ Although generally well tolerated, labetalol has been associated with mild‐to‐moderate aminotransferase elevations in up to 8% of treated patients, reportedly more frequently than with other β‐blockers. These abnormalities are usually transient, asymptomatic, and may resolve despite continued therapy. In contrast, rare but potentially severe, clinically apparent idiosyncratic liver injury from labetalol has been reported in isolated case reports and case series. Labetalol‐induced liver injury is typically hepatocellular in pattern, with a latency of approximately 4‐16 weeks; progression to acute liver failure or liver transplantation has been described. ⁴ , ⁵ The U.S. product label includes warnings for hepatic necrosis and death, with discontinuation advised when drug‐related injury is suspected. ⁶ Historical experience with dilevalol, the R,R‐isomer of racemic labetalol that was withdrawn following hepatotoxicity reports, further motivates careful appraisal. ⁷

Drug‐induced liver injury (DILI) can progress rapidly, and drug withdrawal remains the primary intervention. Despite decades of case reports and regulatory warnings, no comprehensive synthesis has integrated clinical, pharmacovigilance, and mechanistic evidence to better characterize this safety signal. In this study, a fatal case of suspected labetalol‐induced acute liver failure is presented, and available evidence is synthesized through a Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA)‐guided systematic review and a U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) disproportionality analysis to characterize the clinical phenotype of labetalol hepatotoxicity and assess its reporting signal relative to all other drugs and to other β‐blockers.

Case Report

A 25‐year‐old pregnant woman (gravida 2, TPAL 0‐0‐1‐0) presented to her primary care physician in December after a positive home pregnancy test in September. She was diagnosed with hypertension and commenced on nifedipine, with labetalol added shortly thereafter at a dose of 400 mg four times daily. In January, at an estimated gestational age of 32 weeks, she was reviewed at a high‐risk pregnancy clinic and found to have hypertension with pre‐eclampsia (blood pressure 140/90 mmHg). Her expected delivery date was in March. Labetalol therapy was continued, and follow‐up was arranged.

In late February, the patient went into labor. Due to fetal malposition, she underwent Caesarean delivery and gave birth to a healthy 2.4 kg female infant at 36 weeks’ gestation. The patient and infant were discharged after 3 days, and antihypertensive therapy with labetalol and nifedipine was continued postpartum.

In May, the patient presented to the emergency department of a regional hospital with complaints of abdominal discomfort and non‐specific abdominal tenderness on examination. Laboratory investigations demonstrated markedly elevated alanine aminotransferase (ALT) of 1000 U/L and aspartate aminotransferase (AST) of 500 U/L, with a total bilirubin of 132 µmol/L. Abdominal ultrasound showed no evidence of biliary obstruction. Labetalol therapy was not discontinued, and the patient was discharged with gastroenterology follow‐up.

On June 17, the patient re‐presented to a community hospital with worsening symptoms, including frank confusion, jaundice, and progressive clinical deterioration. Laboratory investigations demonstrated severe hepatic dysfunction with ALT 949 U/L (reference 17‐63 U/L), alkaline phosphatase 140 U/L (50‐136 U/L), total bilirubin 390 µmol/L (3.4‐12 µmol/L), international normalized ratio (INR) 2.5, and ammonia 400 µmol/L (<35 µmol/L). She was transferred the same day to a tertiary care center for assessment of acute liver failure and possible transplantation.

On admission to the hepatology service, investigations confirmed hyperbilirubinemia, markedly elevated transaminases, and coagulopathy. Laboratory values included ALT 1120 U/L, total bilirubin 410 µmol/L, INR 2.4, and ammonia 723 µmol/L, consistent with fulminant hepatic failure. Viral hepatitis serology, autoimmune markers, and toxicology screens (including recreational drugs and common hepatotoxins) were negative. Causality assessment using the Roussel Uclaf Causality Assessment Method (RUCAM) yielded a score of 5, consistent with a possible DILI attributed to labetalol.

Her past medical history was unremarkable apart from a therapeutic termination at age 18. She reported regular cannabis and tobacco use and occasional methamphetamine use, although alcohol and stimulant use during pregnancy was described as infrequent. She denied occupational exposure to hepatotoxins. Her medications included prenatal vitamins, nifedipine, and labetalol.

Despite aggressive supportive care, she remained hemodynamically unstable and developed refractory cerebral oedema. Her condition worsened, and her Glasgow Coma Scale (GCS) score declined to 3. Due to her instability, she was not considered a suitable candidate for liver transplantation. Following multidisciplinary consultation, the decision was made in conjunction with her family members to withdraw life‐sustaining measures, and she passed away shortly thereafter.

Methods

This review followed PRISMA 2020 guidelines ⁸ and was prospectively registered in PROSPERO (ID: CRD420251006187). ⁹

Case Report

This case report involved de‐identified patient data and was therefore not considered human subjects research under Western University Research Ethics Board (WREM) policy. Formal REB approval and written consent were not required. The case was reviewed under the authority of the Ontario Regional Coroner's Office in accordance with local regulations.

Systematic Review of Labetalol‐Induced Hepatotoxicity

Case reports, mechanistic studies, and pharmacovigilance analyses reporting hepatotoxicity associated with labetalol in humans were included. Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome cases and non‐human studies were excluded due to the confounding risk of determining causality and interspecies differences limiting translational applicability, respectively. Articles without primary data were also excluded. A comprehensive search of the following databases was conducted from inception to December 2025: MEDLINE (Ovid), Embase (Ovid), CINAHL, the Cochrane Library, PubMed, with Google Scholar used as a supplementary search source. Search strategies are presented in Table S1. Reference lists of the included studies were also hand‐searched to identify additional eligible records.

The study selection process is illustrated in the PRISMA flowchart generated through Covidence (Figure 1). Titles and abstracts were independently screened by two reviewers (EDH, MJR) using Covidence. Full‐text review was performed by a single reviewer (EDH), with oversight and verification by a second reviewer (MJR) for accuracy and consistency. Discrepancies were resolved by a third reviewer (EU). Data were extracted by one reviewer (EDH) and verified by a second using a standardized form (MJR). Risk of bias assessments were conducted using the Murad et al. tool for case reports and a modified ToxRTool for mechanistic studies to inform interpretation. ¹⁰ , ¹¹ These assessments are provided in Tables S3 and S4.

Figure 1.

PRISMA 2020 flow diagram of study selection. This diagram illustrates the systematic review process for identifying, screening, and including case reports of labetalol‐induced hepatotoxicity. Numbers for each step represent articles or cases remaining after exclusions.

Given the heterogeneity and limited granularity of the available evidence, no quantitative meta‐analysis was planned. Although the registered protocol anticipated evaluation of the magnitude of risk and risk factors, methodological refinements were made after protocol registration to reflect the final evidence based and analytic approach. The final evidence base consisted predominantly of case reports, mechanistic studies, and pharmacovigilance data without denominators sufficient for incidence estimation or comparative risk quantification. Accordingly, the evidence was synthesized narratively. Clinical case reports were summarized descriptively across predefined domains, and summary statistics were calculated for descriptive purposes only, not as incidence or risk estimates. Risk‐of‐bias assessments informed interpretation but were not used as exclusion criteria. Clinical findings were interpreted alongside mechanistic and pharmacovigilance evidence to assess overall consistency and biological plausibility of the association.

Pharmacovigilance Signal Detection Using FAERS

Spontaneous adverse event reports from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) were retrieved for the period 2020Q1‐2025Q1. Data processing and selection of reports is illustrated in Figure 2. Data were deduplicated according to FDA's recommended procedure: for duplicate CASEIDs, the report with the most recent FDA_DT was retained, and if dates were identical, the highest PRIMARYID was selected. The DEMO, DRUG, and REAC files were merged by PRIMARYID. Drug names were standardized to the active ingredient “labetalol,” collapsing brand and generic variants. Primary suspect (PS) labetalol reports were identified from the DRUG file. Hepatotoxicity events were defined using a manually curated list of 50 MedDRA Preferred Terms (PTs) using both a narrow definition (covering acute and chronic hepatic injury) and a broad definition (which additionally included liver‐related laboratory abnormalities), ¹² the full list is provided in Table S2.

Figure 2.

Workflow of FAERS data processing for disproportionality analysis of labetalol‐associated hepatotoxicity. This figure demonstrates stepwise filtering and deduplication of FAERS reports to generate the analytic dataset for disproportionality analysis. DEMO, DRUG, and REAC files were deduplicated according to FDA guidance. “n” = number of records remaining after each step.

Two disproportionality analyses were conducted. The first assessed disproportionate reporting of hepatotoxicity with labetalol compared to all other drugs in FAERS. The second restricted the comparator to other β‐blockers, defined by generic and brand names of commonly used agents (atenolol, metoprolol, propranolol, carvedilol, bisoprolol, nebivolol, nadolol, sotalol, timolol, acebutolol, betaxolol, pindolol, esmolol, and carteolol), excluding labetalol. Only primary suspect reports were retained for both labetalol and the comparator drug.

For each PT, two‐by‐two contingency tables were constructed to calculate proportional reporting ratios (PRR) and reporting odds ratios (ROR) with 95% confidence intervals. ¹³ , ¹⁴ Let “a” represent the number of primary suspect reports with both labetalol and the event, “b” the number with labetalol but not the event, “c” the number with the event but not labetalol, and “d” all remaining reports.

The ROR was calculated as:

$$\mathrm{ROR}=\frac{\mathrm{a}\times \mathrm{d}}{\mathrm{b}\times \mathrm{c}}$$

With 95% confidence intervals estimated using the Wald method on the log scale:

$$95\%\mathrm{CI}={\mathrm{e}}^{\ln \left(\mathrm{ROR}\right)\pm 1.96\sqrt{\frac{1}{\mathrm{a}}+\frac{1}{\mathrm{b}}+\frac{1}{\mathrm{c}}+\frac{1}{\mathrm{d}}}}$$

The PRR was calculated as:

$$\mathrm{PRR}=\frac{\mathrm{a}/\left(\mathrm{a}+\mathrm{b}\right)}{\mathrm{c}/\left(\mathrm{c}+\mathrm{d}\right)}$$

$$95\%\mathrm{CI}={\mathrm{e}}^{\ln \left(\mathrm{PRR}\right)\pm 1.96\sqrt{\frac{1}{\mathrm{a}}-\frac{1}{\mathrm{a}+\mathrm{b}}+\frac{1}{\mathrm{c}}-\frac{1}{\mathrm{c}+\mathrm{d}}}}$$

Signal‐detection thresholds were specified a priori based on established pharmacovigilance practice and published FAERS analyses, including prior hepatotoxicity‐focused disproportionality studies. ¹⁵ For each drug–event pair, at least three primary suspect reports (α ≥ 3) were required for inclusion in the analysis. A signal was considered present if the lower bound of the 95% CI for the ROR exceeded 1, and if PRR ≥ 2.

To evaluate the statistical robustness of observed signals, we additionally calculated the information component (IC) using the Bayesian Confidence Propagation Neural Network (BCPNN) framework. ¹⁶ The IC provides a shrinkage‐based disproportionality metric that is less sensitive to sparse data; a signal was considered statistically sound when the credibility interval (IC₀₂₅) exceeded zero. All analyses were performed using R (v4.5.1).

Completed PRISMA 2020 and READUS‐PV checklists are provided in the Supplementary Material.

Results

Descriptive Analysis of Labetalol‐Associated Hepatotoxicity Case Reports

Following a systematic review of the literature spanning from the inception of labetalol's medical use in 1984 to present time, 27 case reports are presented (summarized in Table 1). ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ The median age of hepatic injury onset was 39 years (range: 15‐73 years). Most patients were female (81%), of whom 36% were pregnant or postpartum at the time of presentation. ¹⁷

Table 1.

Patient and Case Characteristics of Reported Labetalol‐Induced Hepatotoxicity. This Table Summarizes Demographics, Pregnancy Status, Latency to Onset, Key Laboratory Findings, Clinical Outcomes, and Concurrent Medications From Published Case Reports Identified in the Systematic Review

						Outcome
		Age, Sex		Daily Dose	Time to Onset	Time to Recovery
Case [ref.]	Year	y	Race	mg	d	D	Non‐recovery Outcome	Treatment Plan
1 18	1986	49, female	African American	300	60	‐	Death 4 days post‐liver transplant	Labetalol discontinuation; liver transplant
2 18	1987	63, female	African American	200	77	‐	Death 20 days post hospitalization	NR
3 18	1985	37, male	White	600	189	‐	Death	NR
4 18	1985	65, female	White	400	56	NR	Hospitalized	NR
5 18	1987	57, female	White	50	53	NR	Hospitalized	NR
6 18	1988	54, female	White	100	48	NR	Hospitalized	NR
7 18	1986	70, female	White	‐	21	NR	Hospitalized	NR
8 18	1986	38, male	White	400	76	NR	Hospitalized	NR
9 18	1985	66, female	White	400	128	NR	Hospitalized	NR
10 18	1989	64, female	White	200	70	NR	Hospitalized	NR
11 18	1989	51, female	African American	200	30	NR	Hospitalized	NR
12 27	1991	73, male	NR	400	60	‐	Death 14 days post‐hospitalization	All medications discontinued; hydration, vitamin K, and lactulose initiated
13 23	2002	50, male	Asian	400	7	17	‐	Labetalol discontinued
14 19	2007	34, female a	Hispanic	1600	30	7	‐	Labetalol discontinued; hydrochlorothiazide 25 mg daily
15 21 , 22	2007	51, female	African American	900	90	‐	Liver transplant; stable 8 months post‐transplant	Home meds discontinued; oral nicardipine for blood pressure; liver transplant
16 28	2010	15, male	NR	400	60	60	‐	Labetalol discontinued
17 17	2015	41, female a	NR	60	84	14	‐	Labetalol discontinued
18 20	2015	39, female a	NR	NR	28	‐	Patient became acutely encephalopathic and developed acute kidney injury; synthetic liver function normalized at ≈2 weeks, but cirrhosis observed at 8 months post event	Discontinued medications; lactulose for encephalopathy, obstetric management (delivery, D&C)
19 32	2021	37, female a	NR	NR	35	‐	Became encephalopathic and went into acute liver failure; liver transplant	Labetalol discontinued; liver transplant
20 31	2021	38, female	NR	NR	30	42	‐	Prednisone 60 mg daily and tapered over 4 months: budesonide 3 mg daily for maintenance and withdrawal at 12 months
21 25	2022	36, female	NR	NR	53	66	‐	Labetalol discontinued
22 24	2022	35, female	NR	NR	140	56	‐	Labetalol discontinued; Prednisolone 40 mg daily and tapered
23 30	2024	34, female a	NR	NR	150	14	‐	Self‐discontinued
24 26	2024	29, female	NR	NR	365	28	‐	Labetalol discontinuation; short course of glucocorticoids
25 29	2024	37, female a	NR	NR	330	90	‐	Labetalol discontinued; Solu‐Medrol 250 mg for 3 days, transition to oral steroids (prednisone for 3 months);
26 34	2020	39, female a	NR	200	205	70	‐	Labetalol discontinuation; switch to nifedipine for hypertension
27 35	2025	35, female a	NR	400	90	35	‐	Labetalol discontinued

		AST	ALT	ALP	TB
Case	Initial symptoms	←U/L→			µmol/L	INR	Rechallenge	Interesting case notes
1	Jaundice	1410	1041.6	180	308	NR	‐	Concurrent furosemide, prazosin, and nifedipine
2	Gastrointestinal symptoms; dark urine	1252.8	1828.8	205.2	62	NR	+	Asymptomatic cholelithiasis (no obstruction); prior hepatitis B serology
3	Jaundice; gastrointestinal symptoms; dark urine	2013.6	1095.6	216	168	NR	‐	Concurrent alcohol use
4	Abnormal laboratory tests	271.8	1050	174	14	NR	+	Peripheral eosinophilia noted
5	Jaundice; pruritus	796.2	661.2	186	220	NR	+	Liver biopsy revealed higher cholestatic features than others
6	Jaundice	1400.4	309.6	138	130	NR	+	‐
7	Jaundice	2474.4	4550.4	120	20	NR	+	Leukocytosis (WBC 21 000/mm3) noted
8	Jaundice	781.2	1956	102	148	NR	+	‐
9	Jaundice	1040.4	1500	294	140	NR	+	Mild atypical lymphocystis (2%) noted
10	Jaundice; pruritus; rash	1290	925.2	258	324	NR	+	Maculopapular rash noted
11	Jaundice; vomiting; dark urine	1350	1900.2	192	86	NR	+	‐
12	Jaundice; anorexia; dark urine; hepatomegaly	4230	4590	346	444.6	>1.5	NR	Comorbid gout and hyperlipidemia; Concurrent hydralazine, furosemide, gemfibrozil, and probenecid
13	Elevated liver enzymes	85	620	88	18.81	NR	NR	Hypertensive intracerebral hemorrhage and a history of chronic hepatitis B infection
14	Dark urine; elevated liver enzymes	669	1119	289	8.55	NR	NR	Severe preeclampsia; concurrent prenatal vitamins and nitrofurantoin; prior cholecystectomy
15	Jaundice; dark urine; gastrointestinal symptoms; elevated liver enzymes; anorexia	5753	4026	NR	410.4	2.0	NR	Concurrent hydrochlorothiazide, trandolapril, and spironolactone; history of methyldopa‐induced hepatitis 17 years prior
16	Jaundice; elevated liver enzymes; dark urine; hyporexia; vomiting	905	804	314	220.59	“normal”	NR	Adolescent male; post‐ aortic coarctation surgery; four RBC blood transfusions during surgery
17	Elevated liver enzymes	622	1133	110	11.46	“normal”	NR	Postpartum; history of fibromyalgia and bronchial asthma; concurrent use of glucosamine, ibuprofen and iron; transient ANA positivity and IgA elevated
18	Jaundice; Elevated liver enzymes	2701	1406	159	304	3.1	NR	Twin pregnancy (20 wks, IVF); comorbid T2D and obesity; concurrent labetalol and methyldopa; possible prior eosinophilic pneumonia due to labetalol ≈13 years earlier; autoimmune serology (ANA +, IgG/IgA↑); cirrhosis 8 months post injury
19	Right upper quadrant pain; elevated liver enzymes	1179	1545	211	99.18	1.8	+	Pregnant at 13 weeks; acute encephalopathy → urgent liver transplant; prior acute liver injury 7 years prior during previous pregnancy
20	Jaundice; nausea; fatigue	1218	833	NR	391.59	1.7	NR	Obesity; herbal supplement use; ASMA+, IgG ↑
21	Jaundice; scleral icterus	2042	1402	NR	206.91	NR	NR	ANA+, IgG ↑
22	Jaundice; gastrointestinal symptoms; pruritus; anorexia; elevated liver enzymes	1419	1264	294	85.5	1.4	+	Co‐morbid Hashimoto's thyroiditis, anxiety, and obesity; ANA+, IgG mildly↑
23	Malaise; scleral icterus; nausea; right upper quadrant pain; elevated liver enzymes	1294	1589	229	143.64	1.3	NR	Postpartum; ANA+; chronic DILI after labetalol; LFTs improved after discontinuation; relapse in next pregnancy but normalized by 34 weeks
24	Jaundice; fatigue	>1500	3458	278	124.83	NR	NR	‐
25	Diarrhea; scleral icterus	1353	1305	237	238.86	1.3	NR	Postpartum (≈2 mo); Concurrent insulin use
26	Lower left quadrant pain; elevated liver enzymes	524	1099	86	8.55	NR	NR	G2P1011 at 27+ 2 weeks gestation; started labetalol pre‐conception; history myomectomy; reported non‐adherence (missed 3 days)
27	Right upper quadrant pain; elevated liver enzymes	303	573	“normal”	“normal”	NR	NR	Obesity; pre‐existing hepatic steatosis; history of unprovoked deep vein thrombosis (3 years prior); 30 weeks’ gestational age at presentation; concurrent use of prenatal vitamins and vaginal progesterone

“‐” = not applicable; “NR” = not reported.

^aWoman is postpartum or pregnant.

Labetalol was most commonly prescribed for hypertension (n = 8). Additional indications included hypertension in pregnancy (n = 4), preeclampsia (n = 2), postpartum hypertension (n = 1), postoperative hypertension following aortic coarctation repair (n = 1) in the only reported paediatric patient (Case 16; 15‐year‐old male), and symptomatic palpitations during pregnancy (n = 1). Daily doses ranged from 50 to 1600 mg (median: 400 mg). Time to onset of hepatotoxicity ranged from 7 to 365 days, with a median of 60 days following treatment initiation.

Jaundice was the most frequently reported presenting symptom (n = 17), followed by dark urine (n = 7), elevated liver enzymes (n = 11), and gastrointestinal symptoms such as nausea, vomiting, or abdominal pain (n = 11). Less commonly reported symptoms included pruritus (n = 3), fatigue (n = 2), scleral icterus (n = 3), and hyporexia or anorexia (n = 4).

All cases demonstrated a hepatocellular injury pattern (R factor >5). Median aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations were 30‐ and 28‐fold the upper limit of normal (ULN), respectively, calculated using sex‐specific ULN values in accordance with Mayo Clinic recommendations. ³⁶ ALT exceeded AST in 56% of cases. Alkaline phosphatase (ALP) elevations were mild (median: 1.8‐fold ULN). Total bilirubin was elevated in most patients (range: 8.6‐444.6 µmol/L; median: 141.8 µmol/L; ≈6.9 × ULN). The distribution of liver enzyme and bilirubin elevations across individual cases is shown in Figure 3. Direct bilirubin values were reported in four cases, with direct‐to‐total bilirubin ratios exceeding 0.5 in three, consistent with conjugated hyperbilirubinemia. International normalized ratio (INR) values were available in ten cases (range: 1.3‐3.1; median: 1.7).

Figure 3.

Heatmap of liver function test elevations. This heatmap displays fold‐elevation values for serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin across 27 published case reports. Each row represents an individual case. The intensity of cell color corresponds to the magnitude of fold elevation above the upper limit of normal (ULN), with values displayed numerically within each cell. Gray cells indicate missing or unreported values, denoted by “NA” meaning “not available”. ULN reference values were sourced from the Mayo Clinic Laboratories and are as follows: ALT: 55 U/L (male), 45 U/L (female); AST: 48 U/L (male), 43 U/L (female); ALP: 129 U/L (male), 104 U/L (female); Total bilirubin: 20.52 µmol/L (sex‐independent).

Reporting of diagnostic investigations varied across case reports. Demographics, presenting symptoms, time to onset, aminotransferase values, total bilirubin levels, and viral hepatitis serologies were reported consistently, whereas INR (41%), autoimmune serologies (52%), liver biopsy findings (56%), and imaging details (52%) were inconsistently documented (Figure 4).

Figure 4.

Reporting of key diagnostic variables in published labetalol hepatotoxicity cases (n = 27). This bar chart summarizes the reporting frequency of commonly assessed parameters across published case reports of labetalol‐associated hepatotoxicity. ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase; INR = international normalized ratio; CBC = complete blood count; US = ultrasound; CT = computed tomography; MRI = magnetic resonance imaging

Sixteen patients met Hy's Law criteria. ³⁷ Several additional cases met biochemical thresholds but had potential confounding factors, including pre‐existing liver disease or prior hepatic injury (Cases 2, 13, 15, 19, and 27) or concomitant exposure to other potentially hepatotoxic agents such as hydralazine (Case 12) or methyldopa (Case 18).

Reported comorbidities included hypertension, obesity, diabetes, asthma, fibromyalgia, and pre‐existing liver disease. Extrahepatic manifestations were infrequently reported and included encephalopathy (n = 2), rash (n = 1), peripheral eosinophilia (n = 1), and atypical lymphocytosis (n = 1). Autoantibody positivity and elevated immunoglobulin levels were reported in several cases. Viral hepatitis serologies were negative in all but two patients with chronic hepatitis B infection.

Clinical outcomes included death (n = 4) and liver transplantation (n = 2). All fatal cases reported in the literature occurred prior to 1991. Among non‐fatal cases with available follow‐up, eight resolved following drug discontinuation (median recovery time: 26 days), while five required adjunctive therapy, most commonly corticosteroids or lactulose (median recovery time: 42 days). Rechallenge with labetalol was documented in 13 patients, with recurrence of liver injury reported in eleven. Two rechallenges were reported as negative; both occurred in patients who subsequently experienced clinical deterioration and fatal outcomes. No intentional rechallenges have been reported since 1990.

Pregnancy‐Associated Cases

Eight cases of labetalol‐induced hepatotoxicity occurred in pregnant or postpartum individuals (mean age: 37 years). Onset ranged from 12 weeks’ gestation to 5 months postpartum, without a consistent temporal pattern. Presenting symptoms were similar to those observed in non‐pregnant patients, although right upper quadrant and left lower quadrant pain were reported more frequently. Two patients developed fulminant hepatic failure; one underwent transplantation during the first trimester, and one progressed to cirrhosis following twin deliveries. Five cases were resolved following drug withdrawal, and no maternal deaths were reported in this subgroup.

Histopathological Findings

Liver biopsy findings were reported in 15 cases. The predominant histopathological pattern was hepatocellular injury, characterized by varying degrees of hepatocellular necrosis, including massive or submassive necrosis in several cases and zonal necrosis in others. Piecemeal necrosis or bridging necrosis was also reported, indicating more severe hepatic injury in some patients. Inflammatory changes were common and typically consisted of portal or periportal infiltrates composed primarily of lymphocytes and neutrophils, with occasional reports of eosinophils. Other reported features included hepatocyte ballooning degeneration, cholestatic changes, fatty change, or fibrosis. Cases with cholestatic features often involved concomitant medications. One biopsy demonstrated extensive hepatocyte loss with approximately 40% necrosis, while another reported preserved hepatic architecture without fibrosis or steatosis despite biochemical and clinical evidence of liver injury. Detailed histopathological findings for individual cases are summarized in Table S5.

Summary of Labetalol‐Associated Hepatic Injury Cases in FAERS

Across the entire FAERS database, 6210 reports involving labetalol were identified. Reports peaked in 1986, declined, and rose again after 2017, with a secondary peak in 2024 (Figure 5). Of these, 363 reports met the predefined hepatotoxicity criteria (50 MedDRA PTs).

Figure 5.

Temporal trends in FAERS reporting, 1985‐2025. Annual counts of adverse event reports meeting predefined hepatotoxicity criteria (50 MedDRA preferred terms) in which labetalol was listed as a suspect drug. Black dots represent yearly case counts; the gray dotted line indicates a smoothed trend. Counts reflect spontaneous reporting and do not represent incidence.

Most of these reports originated from healthcare professionals (60.8%), followed by consumers (35.9%). Females accounted for 56.6%, males 31.5%, with sex not specified in 11.9%. The majority were aged 18‐64 years (58.0%), with smaller proportions in pediatrics (8.6%) and older adults (11.1%).

The most frequently reported hepatic PTs were AST increased (21.3%), ALT increased (17.4%), hepatic function abnormal (16.3%), hepatic cytolysis (11.1%), and hepatitis (10.8%). Other notable terms included jaundice (10.2%), DILI (9.7%), and hyperbilirubinemia (9.4%). Severe presentations were also documented, including hepatic necrosis (6.1%), acute hepatic failure (2.7%), and liver transplant (1.7%). Overall, 92.6% of cases were classified as serious. Outcomes included hospitalization (n = 197), death (n = 65), and life‐threatening events (n = 13). Fatal cases occurred intermittently over the study period, with clusters in 1985‐1988 (n = 12), 2022 (n = 6), and a peak in 2023 (n = 26), mirroring the temporal distribution of overall case reporting.

Signal Detection and Disproportionality Analysis in FAERS (2020Q1‐2025Q1)

From Q1 2020 through Q1 2025, 7,802,376 deduplicated FAERS reports were available. Among these, 620 reports identified labetalol as the primary suspect drug (0.008% of all reports). In these cases, the median age was 35 years (IQR 29‐52.2), and females accounted for 63.7% of patients. The five top co‐reported drugs with labetalol included nifedipine (n = 131), magnesium sulfate (n = 84), hydralazine (n = 61), magnesium (n = 49), and amlodipine (n = 41). Within this subset, 40 overlapped with hepatic PTs. Within the hepatic subgroup, the median age was 36 years (IQR 34‐37), and nearly all patients were female (89%). Reports in this subgroup averaged 2.15 drugs and 2.45 reaction terms each.

Disproportionality analysis identified four PTs with positive signals: DILI, autoimmune hepatitis, acute hepatic failure, and hyperbilirubinemia (Table 2).

Table 2.

Disproportionality Metrics for Hepatic Adverse Events Associated with Labetalol in FAERS (2020Q1‐2025Q1). Metrics Calculated Using Deduplicated DEMO, DRUG, and REAC Files Following FDA Guidance

Hepatic PT = Any preferred term (PT) related to hepatic injury from a predefined list, based on terms commonly used in FAERS to describe liver injury and related disorders; IC = information component; IC025 = lower bound of the 95% credibility interval; PRR = proportional reporting ratio; ROR = reporting odds ratio.

Labetalol Versus All Other Drugs

For DILI, 26 reports were identified compared with 14 408 reports for all other drugs, yielding a PRR of 22.71 (95% CI: 15.58‐33.09) and an ROR of 23.66 (95% CI: 15.97‐35.05). The IC was 3.15 (IC025 = 2.48), confirming a strong statistical signal.

Autoimmune hepatitis showed the most pronounced disproportionality signal, with 12 labetalol‐associated reports compared to 2526 for all other drugs (PRR 59.78, 95% CI: 34.09‐104.83; ROR 60.94, 95% CI: 34.37‐108.05; IC 4.55, IC025 = 2.76).

For acute hepatic failure and hyperbilirubinaemia, only three labetalol cases were reported for each PT. While both produced elevated PRR and ROR values, the IC lower bounds were negative, indicating weaker statistical robustness.

Labetalol Versus Other β‐Blockers

When restricted to β‐blocker comparators, signals for DILI (PRR 14.07, 95% CI: 8.87‐22.31; ROR 14.64, 95% CI: 9.11‐23.54; IC 1.89, IC025 = 1.41) and autoimmune hepatitis (PRR 175.32, 95% CI: 39.32‐781.66; ROR 178.76, 95% CI: 39.92‐800.45; IC 3.35, IC025 = 2.31) remained significant. Acute hepatic failure (PRR 17.53, ROR 17.61) and hyperbilirubinemia (PRR 9.74, ROR 9.78) again showed elevated point estimates, but IC025 values were negative, suggesting statistical fragility due to sparse counts.

In Vitro and Mechanistic Evidence of Labetalol‐Induced Hepatotoxicity

High‐content cellular imaging assays in primary human hepatocytes identified labetalol as DILI‐positive, with elevated reactive oxygen species (ROS) and lipid accumulation, while moderately affecting mitochondrial membrane potential and intracellular glutathione levels. ³⁸

Transporter assays showed no significant inhibition of MRP2 or OATP1B1, and only slight inhibition of UGT1A1. ³⁹ CYP3A4‐overexpressing HepG2 cells did not demonstrate increased cytotoxicity, suggesting phase I metabolism through CYP3A4 was not a major contributor. ⁴⁰ The attention has more recently turned to phase II enzymes, particularly sulfotransferases (SULTs), as potential mediators of hepatotoxicity. Studies in primary hepatocytes confirmed the detection of a glutathione (GSH) conjugate of labetalol and subsequently reported that treatment with 2,6‐dichloro‐4‐nitrophenol, a broad‐spectrum SULT inhibitor, significantly reduced the formation of said GSH conjugate as well as hepatocyte cytotoxicity. ⁴¹

Pregnancy‐related hormones (PRH), including estradiol, estetrol, progesterone, and cortisol, upregulated the expression of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) in human hepatocytes, enhancing glucuronidation of labetalol. ⁴² This effect was largely driven by estradiol. In contrast, PRH had no significant effect on UGT2B7 expression or function. Additional in vitro work showed minimal interaction between labetalol and folate supplementation, commonly used in pregnancy, with only slight reductions in viability. ⁴³

An in‐silico study of MDR1 transporter variants demonstrated stronger binding of labetalol and dilevalol to the Q725R variant, found exclusively in European populations. Variant‐specific modeling showed the SNP to be localized within the proposed binding pocket of MDR1, potentially altering drug‐transporter interactions. ⁴⁴

Discussion

The present case illustrates a severe manifestation of suspected labetalol‐associated hepatotoxicity occurring in the postpartum period, with progressive hepatocellular injury culminating in acute liver failure several months after treatment initiation. Although most reported cases occur within 2‐16 weeks of exposure, delayed presentations have been described in idiosyncratic drug reactions and may reflect immune‐mediated mechanisms or triggering cofactors such as intercurrent infection. ⁴⁵ Alternative causes of liver injury were considered. Nifedipine is a recognized but rare cause of drug‐induced liver injury and therefore cannot be fully excluded as a potential contributor in this case; however, published reports have frequently described cholestatic or mixed features, which differ from the predominantly hepatocellular phenotype observed here. The patient also reported intermittent recreational drug use; however, these exposures have not been consistently linked to this pattern of liver injury. Apart from female sex, which predominates in reported cases, no clear clinical risk factors were identified. More broadly, genetic susceptibility has been implicated in DILI, although genetic variants were not assessed in the present case.

Findings across multiple evidence streams are broadly consistent with labetalol‐associated hepatotoxicity. In the case literature, the injury pattern is consistently hepatocellular, with frequent fulfilment of Hy's law ³⁷ and recurrent autoimmune‐like features. Historical rechallenge was positive in most attempts, which strengthens causal attribution but also highlights the risk of recurrence; most instances were accidental and predate contemporary diagnostics and therefore do not imply clinical safety of re‐exposure. In FAERS (2020Q1‐2025Q1), disproportionality signals were robust for the terms DILI and autoimmune hepatitis, and these signals persisted even when the comparator was restricted to other β‐blockers. Although signals for acute hepatic failure and hyperbilirubinemia were elevated, they were statistically fragile due to sparse reporting.

Structural and Metabolic Considerations of Labetalol

Labetalol consists of four stereoisomers with distinct receptor‐binding properties, whereas most β‐blockers are single isomers or simple racemates with less stereoselective metabolism. ⁴⁶ Stereoisomers may differ in metabolic fate, and the R,R‐isomer dilevalol, historically associated with severe hepatotoxicity, illustrates the potential for stereochemistry to influence risk. ⁷ However, no established in vivo mechanisms selectively enrich the RR‐isomer with racemic labetalol, and any such contribution to hepatotoxicity remains speculative.

Labetalol also differs structurally from most β‐blockers, which typically contain a single aromatic ring. Labetalol possesses two aromatic rings; a feature associated with increased lipophilicity and hepatic metabolism. Drugs with multiple aromatic systems have been linked to a higher likelihood of hepatotoxicity. ⁴⁷ One of labetalol's rings includes an ortho‐hydroxy group adjacent to an amide linkage, creating a salicylamide‐like motif. This moiety undergoes glucuronidation and may be oxidized to quinone‐like intermediates. ⁴⁸ , ⁴⁹ Together with the second aromatic ring, these structural features plausibly increase the formation of reactive metabolites and immune‐mediated injury. These mechanisms remain hypothetical but are consistent with experimental findings in hepatocyte assays. ³⁸ , ⁴¹

Susceptibility in Pregnancy or Post‐Partum States

Maternal hormonal changes during pregnancy alter the expression and activity of hepatic drug‐metabolizing enzymes, including upregulation of UGT1A1 and shifts in cytochrome P450 isoforms, which may influence the balance between detoxification and bioactivation. ⁵⁰ , ⁵¹ , ⁵² Although glucuronidation is generally protective, oxidative stress conditions could favor alternative pathways such as sulfotransferase‐mediated bioactivation, generating electrophilic intermediates requiring glutathione conjugation for detoxification. Pregnancy also modulates hepatic transporter activity and maternal immune function, potentially affecting the clearance of reactive metabolites, promoting intrahepatic accumulation, and altering susceptibility to immune‐mediated injury. Beyond hepatic effects, pregnancy shifts the maternal immune system toward a Th2‐dominant, tolerance‐biased state to protect the fetus, but immune rebound in the postpartum period may increase the risk of autoimmune‐like reactions. ⁵³

The representation of pregnant and postpartum patients in the case literature may also reflect population factors such as comorbidities, maternal age, and liver stress syndromes—intrahepatic cholestasis of pregnancy (ICP), preeclampsia, or HELLP syndrome—each of which can independently elevate liver enzymes and confound causality. ⁵⁴ Interindividual susceptibility likely reflects host factors such as baseline hepatic reserve, co‐medications, pregnancy physiology, and genetic variants. In silico work implicates the ABCB1/MDR1 Q725R variant in altered transporter interactions with labetalol and dilevalol, though clinical association studies are lacking. ⁴⁴ Maternal risk factors such as obesity may also contribute, as obesity has been linked to altered xenobiotic metabolism and impaired clearance of phenolic compounds. ⁵⁵ Notably, two non‐pregnant patients in the case series were obese. The rising average maternal age further increases comorbidity burdens. Taken together, the pattern of labetalol hepatotoxicity reports may not solely reflect the intrinsic toxicity of the drug, but also the population in which it is most frequently prescribed. These findings should be interpreted as a signal warranting further study rather than definitive evidence of increased risk.

Prior Liver Disease and Susceptibility

Patients with pre‐existing liver disease may represent a subgroup warranting particular attention, though the available case report data are insufficient to establish this as a definitive risk stratum. Pre‐existing hepatic impairment likely lowers the threshold for idiosyncratic injury by depleting functional hepatocyte reserve and diminishing detoxification capacity. Classic human studies in chronic liver disease show that oral, but not intravenous, labetalol exposure is substantially increased due to reduced first‐pass extraction; hemodynamic effects were amplified after oral dosing, and lower serum albumin correlates with higher oral bioavailability. ⁵⁶ Taken together, diminished hepatic reserve combined with increased oral exposure raises the hypothesis that patients with established hepatic disease might benefit from conservative initial dosing, early biochemical surveillance, and prompt withdrawal at the first signal of injury, though this warrants prospective evaluation.

Temporal Trends in FAERS Reports

Recent fluctuations in labetalol reports in the FAERS database more recently could be attributed to a global increase in hypertensive disorders in pregnancy over the past decade, ⁵⁷ which has increased prescribing and thereby expanded opportunities for spontaneous reporting. Because labetalol is recommended as a first‐line antihypertensive in multiple pregnancy guidelines, ¹ , ² , ³ greater exposure would be expected to yield more reports, as spontaneous counts scale with use. ⁵⁸ The use of disproportionality metrics helps account for changes in prescribing volume and allows for the identification of disproportionate reporting patterns within the database. Importantly, FAERS data cannot provide incidence estimates and are vulnerable to biases such as under‐reporting, notoriety, and indication confounding.

Clinical Implications

Recognition that hepatotoxicity has been reported disproportionately with labetalol compared to other β‐blockers is clinically relevant, particularly in pregnant and postpartum patients who often already face liver‐related complications. Current FDA prescribing information warns of hepatic necrosis and death and recommends periodic determination of hepatic laboratory tests, with prompt discontinuation at the first sign of injury. ⁶ Despite this recommendation, routine hepatic monitoring is not commonly implemented in clinical practice, which may delay recognition of injury. Given the clustering of severe reported cases, including those that resulted in transplantation or death, closer vigilance in high‐risk populations may be warranted. Clinicians should maintain a low threshold for discontinuing labetalol if patients develop jaundice, unexplained transaminase elevations, or autoimmune‐like features, and patients should be educated on early warning symptoms. Rechallenge is contraindicated.

Limitations

This work has several limitations that should inform interpretation. The case literature is small, heterogeneous, and variably documented; autoimmune serologies, INR, and direct bilirubin were inconsistently reported, histology was not uniform, and publication bias is likely. The systematic review was deliberately inclusive, and several included reports were abstracts with limited clinical detail; at least two cases involved concurrent exposure to another hepatotoxic drug with a compatible temporal pattern, which complicates single‐agent attribution. In addition, some methodological details evolved after protocol registration in response to the heterogeneity and limited granularity of the available evidence; the final methods are reported transparently in the manuscript. Pharmacovigilance findings cannot establish incidence because spontaneous reports lack denominators and are vulnerable to reporting and indication biases despite comparator restriction and deduplication. Small cell counts render some signals statistically fragile, and preferred term misclassification remains possible. Experimental observations derive from in‐vitro systems and broad enzyme inhibition, which may not mirror in vivo exposures; evidence for reactive intermediates in humans remains indirect. Finally, classic pharmacokinetic studies in hepatic impairment were small and older, limiting generalizability.

Conclusions

Labetalol is widely used as a first‐line antihypertensive agent in pregnancy and the postpartum period, but the findings of this study support concerns that it may, in rare cases, be associated with severe idiosyncratic hepatotoxicity. Across clinical reports, pharmacovigilance data, and experimental studies, the evidence is consistent with a clinically meaningful and biologically plausible safety signal, although causality and mechanism cannot be established definitively from the available data. Greater awareness of this adverse drug reaction can strengthen the benefit‐risk profile of labetalol through earlier recognition and prompt discontinuation when injury is suspected. Prospective registries with interval liver testing, coupled with focused mechanistic and population‐based studies, represent logical next steps to better characterize susceptibility and inform standardized clinical responses.

Author Contributions

Emma D. Hendriksen conceived and designed the study, collected, and analyzed data, and drafted the manuscript. M.J.R. and E.U. provided oversight, contributed to data interpretation, and critically revised the manuscript. All authors approved the final version of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding

This research received no external funding.

Supporting information

Table S1. Search Strategies Used in MEDLINE, Embase, PubMed, CINAHL, Cochrane Library, and Google Scholar

Table S2. MedDRA Preferred Terms (PTs) Used to Define Hepatotoxicity in the FAERS Disproportionality and Descriptive Analysis

Table S3. Methodological Quality (Risk of Bias) Assessment of Included Case Series and Case Reports Using the Murad et al. Tool, Interpreted Qualitatively for Idiosyncratic Drug‐Induced Liver Injury

Table S4. ToxRTool Reliability Assessment of Mechanistic In Vitro Studies Evaluating Labetalol‐Related Hepatotoxicity

Table S5. Histopathologic Findings in Labetalol‐Induced Liver Injury Cases

Table S6. PRISMA 2020 Reporting Checklist

Table S7. READUS‐PV Reporting Checklist

Supporting Information

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.