Homeopathy-medicine induced severe alcoholic hepatitis

Abstract

We present a teetotaler with compensated non-alcoholic fatty-liver-disease related cirrhosis who presented with acute worsening of his chronic liver disease. The acute event was not discernible even after extensive work up and finally a transjugular liver biopsy revealed features suggestive of severe alcoholic hepatitis. The patient and the family denied occult alcohol use when questioned over multiple times and finally, the culprit ‘alcohol’ was found to be the homoeopathy medicines that the patient was consuming over a month for treatment of Gilbert’s syndrome. We retrieved and tested the homoeopathy drug for alcohol content and found an alarming 18% ethanol in the same, confirming our diagnosis.

Background

Alcoholic hepatitis (AH) is a devastating disease that clinically presents with acute onset of jaundice and coagulation failure with ascites or hepatic encephalopathy. The syndrome can present as acute on chronic liver failure which is associated with high mortality in the presence of infections and multiple organ failure.¹ Chronic alcohol abuse appears to be associated with the development of AH, but the key trigger for its development is still unclear, since it has been noted to occur in patients with recent alcohol use and also in binge drinkers, such that environmental and genetic factors may also be central to the event. The amount and duration of alcohol abuse for development of AH depends on the individual patient. Alcohol consumption usually within a 2-month period prior to onset of jaundice is usually noted in patients with AH.² Complementary and complementary medicine use has been on the rise among the general population and patients with chronic disease with regard to presumed ‘safety and efficacy’, without required clinical trials on the same, but through advertisements and promotional activities. Alcohol intoxication linked to Ayurvedic medicine consumption has also been documented in literature. And intoxications and poisonings due to homoeopathic drugs are well known.^{3 4} In this report, we present the interesting but devastating case of a man with compensated cirrhosis and Gilbert’s syndrome (the latter a benign congenital unconjugated hyperbilirubinaemia state) who took homoeopathic medicines for 1 month leading to severe AH that was diagnosed on liver biopsy. Furthermore, we also provide strong evidence, through advanced drug testing, linking the homoeopathy drugs that caused severe drug induced liver injury mimicking AH in the patient.

Case presentation

A 38-year-old obese man (body mass index 35.4), diagnosed with compensated non-alcoholic-fatty-liver-disease related cirrhosis and associated Gilbert’s syndrome was prescribed Homoeopathic-medication (figure 1A) for 1 month for treatment of unconjugated hyperbilirubinaemia. Paternal family history of heart disease and fatty liver disease was significant. The baseline serum total bilirubin prior to starting the homoeopathic drugs was 4.2 mg/dL (normal up to 1.2) with direct bilirubin 0.6 mg/dL (normal 0.1–0.4). After consuming the medicines for a period of 2 weeks, due to feeling of drowsiness, slurring of speech and lethargy, akin to ‘intoxication’, the medication frequency was modified by the treating homoeopath after which liquid formulation was decreased and quantity of tablets increased to five per hour. Two weeks later, the patient noticed yellowish darkening of urine and of eyes, that was associated with bilateral leg swelling. After a visit to the homeopath thereafter, the patient underwent repeat liver test that revealed total bilirubin 12.8 mg/dL with direct bilirubin 9.6 mg/dL, aspartate transaminase 202 IU/L (normal <38), alanine transaminase 82 IU/L (normal <40) and was referred to a higher medical centre for further management. At admission to our liver unit, repeat liver tests showed total bilirubin 29.8 mg/dL with direct bilirubin 15.6 mg/dL, aspartate transaminase (AST) 138 IU/L, alanine transaminase (ALT) 42 IU/L, gamma-glutamyl-transpeptidase 292 IU/L (normal up to 140) with AST:ALT ratio >2 and international normalised ratio 3.8. Blood tests for acute viral hepatitis A, E and for hepatitis B and C were negative. Tests for atypical viral infections such as cytomegalovirus, parvovirus B, herpes simplex and varicella zoster were also non-contributory. Serum ceruloplasmin, 24 hours urinary copper levels, tests for alpha-1-anti-trypsin deficiency, autoimmune liver disease including antinuclear antibody, antismooth muscle antibody, anti-liver-kidney-microsomal antibody and antibodies to liver soluble antigen were all negative. Iron studies were negative while ferritin levels were high (1208 ng/mL, normal 12–300) but mutational studies for haemochromatosis was non-contributory. Blood tests for heavy metals such as lead, mercury, cadmium and arsenic were within normal limits and toxicology screening for drugs, pesticides, insecticides and anabolic steroids were insignificant. In the absence of identifiable causes for the acute event, the patient underwent transjugular liver biopsy after informed consent from the wife. Histopathology of the liver revealed ballooned hepatocytes (figure 1B, arrow), mononuclear-cell-predominant mixed-portal inflammation (figure 1B, dashed arrow), hepatocellular, canalicular and cholangiolar cholestasis (figure 1B, arrow heads), foamy Kupffer cells (figure 1C, arrow), hepatocellular eosinophilic degeneration and extensive pericellular fibrosis (figure 1D, arrows) in the background of cirrhosis suggestive of acute AH. Based on the biopsy findings, further confrontation with the patient and family including sessions with psychologist and a psychiatrist, regarding occult alcohol use was non-contributory. Homoeopathy drugs ingested by the patient were retrieved triple-quadruple-gas-chromatography-coupled-mass-spectroscopic evaluation yielded an alarming cumulative ethanol concentration of 18.3% v/v concentration which was equivalent of fortified wine such as sherry or port. The exact total volume of liquid and number of pills consumed by the patient during the time of homoeopathic treatment could not be ascertained by us since these were discarded after consumption by the patient, except for an explanatory evidence of consumption of ‘many, many bottles’ as per the patient’s spouse, which was also timely linked to the drowsiness and intoxication states experienced by the patient. A final diagnosis of homoeopathy drug induced AH was made, with hepatocellular type of liver injury (R ratio >5) and Roussel Uclaf Causality Assessment Method score was suggestive of probable adverse drug reaction (table 1).

Figure 1.

(A) The culprit homoeopathic drugs retrieved from the patient; liver histopathology showing (B) ballooned hepatocytes (arrow), mononuclear-cell-predominant mixed-portal inflammation (dashed arrow), hepatocellular, canalicular and cholangiolar cholestasis (arrow heads, H&E stain, ×20); (C) foamy Kupffer cells (arrow, H&E stain, ×40), hepatocellular eosinophilic degeneration and (D) extensive pericellular fibrosis (arrows, Masson-trichrome stain, ×20) in the background of cirrhosis suggestive of alcoholic hepatitis.

Table 1.

Causality assessment for drug induced liver injury suggestive of homoeopathy drugs as the acute insult leading to alcoholic hepatitis like insult in the patient

Type of liver injury	Hepatocellular
Time of onset of the event	First exposure
Time from drug intake until reaction onset	5–90 days (+2)
Time from drug withdrawal until reaction onset	≤15 days (+1)
Alcohol risk factor	Absent (0)
Age risk factor	<55 years (0)
Course of the reaction	No improvement (0)
Concomitant therapy	None or information not available (0)
Exclusion of non-drug-related causes	Rule out (+2)
Previous information on hepatotoxicity	Reaction published but unlabelled (+1)
Response to readministration	Not available or not interpretable (0)
Final score	6 (probable adverse drug reaction)

Outcome and follow-up

The patient’s Model for End Stage Liver Disease score was 34 at admission. The patient and family were strongly counselled regarding the need for liver transplantation to increase survival. Nutritional management, antimicrobials and intravenous N-acetyl cysteine were started in the patient after which initial improvement in liver tests were noted, but without further improvement in liver disease severity score. In view of severe AH features on the liver biopsy, the patient was started on oral prednisolone, 40 mg/day in two divided doses. On the eighth day, a Lille Model score was calculated to look for corticosteroid treatment response. The Lille score was 0.98 suggestive of non-response to steroid treatment. In view of high liver disease severity scores and chances of clinical worsening, the patient was referred for further management to a liver transplant centre. In the absence of matching living donors in the family, the patient was listed in the deceased liver donation programme. However, clinical deterioration was rapid with the onset of infections and ultimately the patient developed multiple organ failure and succumbed to his illness 1 month and 12 days after his initial presentation to our unit.

Discussion

We present the rare event of ‘drug induced’ AH in a patient with compensated cirrhosis and provide strong linkage of the acute insult to homoeopathy-drug by state-of-the-art toxicology analysis of the retrieved medicines. Dantas and Rampes demonstrated that the mean incidence of adverse effects of homoeopathic medicines was greater than placebo in controlled clinical trials and a larger incidence of pathogenetic effects in healthy volunteers taking homoeopathic medicines were noted, even though the minor in nature.⁵ Posadzki et al, in their study, demonstrated mild-to-severe adverse events, including four fatalities with homoeopathy medicines. The most common adverse events noted in their cohort of patients were allergic reactions followed by intoxications.⁶ Boatto and colleagues showed that 9 out of 30 subjects gave positive alcohol breath test results (0.11–0.82 g/L) when tests were taken within 1 min after drinking homoeopathic mother tincture.⁷ The WHO has published directives and concerns on the quality control issues for homoeopathic medicines and multiple reports on high alcohol content in homoeopathy medicines have been rife on social and news media.^{8 9} With the rise in use of complementary and alternative medicines among general population, modifiable and avoidable causes for severe liver injury is becoming an important public health concern. At risk patients and the general population need to be educated regarding the fact that complementary and alternative medications are not without side-effects.¹⁰ Governmental regulatory policies and public health awareness on complementary medicine use is an unmet need in developing countries entrenched in use of non-evidence-based complementary medicine practices.

Learning points.

• Gilbert’s syndrome is a benign condition that does not require treatment.

• Homoeopathy is a branch of complementary medicine without proven clinical benefit, but linked to serious adverse events including allergic reactions, poisoning and intoxication.

• In patients presenting with alcohol induced liver injury in the absence of significant alcohol use, a history of complementary medicine use should be sought.

• Physicians caring for patients with chronic diseases must educate the patients, as well as the family regarding use of alternative therapies that could lead to avoidable fatalities.