Hydroxycut^® (herbal weight loss supplement) Induced Hepatotoxicity: A Case Report and Review of Literature

Abstract

Use of supplement and alternative drugs continues to thrive and is becoming an increasing cause of concern since many of these substances may have unexpected or unexplained medical consequences. We present below the first reported case of hepatotoxicity from Hydroxycut^® in Hawai‘i.

ntroduction

Use of dietary supplement is gaining increasing popularity in the United States as a quick fix remedy with allegedly no side effects. Nearly one in five adults in the United States admits to using herbal medications for their diseases or health improvement and 58% of those using these drugs fail to report such use to their primary care physicians.¹

One such common drug is Hydroxycut^® (Lovate Health Sciences Inc.) which has been touted as a safe remedy for weight loss as well as a fat burner. Though it was recalled by the manufacturer after an FDA issued warning on May 1, 2009, the side effect of hepatotoxicity was mentioned to be rare. The FDA warning is based on reports of 23 cases of liver damage including one fatality and a liver transplant.² We are presenting another case with severe liver toxicity in the setting of exposure to Hydroxycut^® and extensive testing to rule out other causes of hepatotoxic disease as well as a biopsy indicative of drug induced hepatotoxicity.

Case Report

A 19-year-old man with no significant past medical history presented to a community medical center with 2-day history of fever, severe fatigue, myalgia, arthralgias and an erythrematous rash over his lower extremities. Patient had started using Hydroxycut^® approximately one week prior to presentation for fat burning and muscle building. He denied any smoking or alcohol use and was on no other prescription or over the counter medication apart from Hydroxycut^® and Myoflex^® cream. His initial exam was notable for toxic appearance and marked icterus with fever up to 103 degrees Fahrenheit. His blood test revealed an Aspartate aminotransferase (AST/SGOT) level of 23 units/liter, Alanine aminotransferase (ALT/SGPT) of 81 units/liter, Alkaline phosphatase 298 units/liter (GGTP-250), white blood cell count of 31 × 10(9)/liter, hemoglobin level of 12.7 gram/deciliter and normal platelet count. Total bilirubin was 7.3 milligram/deciliter, Prothrombin time of 16.7 seconds. Blood cultures, urine analysis, chest X-ray, abdominal ultrasound, Computed Tomography scan and Magnetic Resonance Cholangiopancreatography results were normal. His liver appeared normal in size and texture and there was no evidence of mass, vascular compromise, stone disease, ascites or biliary ductal dilatation. Patient continued to have rising bilirubin levels over the next 3 days and despite antibiotics (Piperacillin and Tazobactum) had persistent fever. On day 4, the patient was transferred to our hospital for possible urgent liver transplant evaluation due to rising total bilirubin of 12.7 milligram/deciliter and Prothrombin time of 21.7 seconds. At presentation he had low-grade fevers with marked icterus, mild right upper quadrant tenderness on deep palpation and a mild erythematous rash over the lower extremities which gradually started to desquamate. Rest of the physical examination including vitals signs was normal and he had no evidence of spider nevi, palmar erythrema, gynecomastia or encepahlopathy. Hepatic profile showed AST at 27 units/liter, ALT at 24 units/liter, alkaline phosphatase at 152 units/liter, bilirubin at 12.4 milligram/deciliter, prothrombin time of 15.4 seconds, ammonia 38 microgram/deciliter, White blood cell count of 34.8 × 10(9)/liter (71 neutrophils and 24 bands), hemoglobin level at 11.2gram/deciliter, platelet count of 237,000/ microliter. Repeat blood cultures and sputum culture as well as urine analysis showed no evidence of infection. Serologies for Hepatitis A, Hepatitis B, Hepatitis C, Anti mitochondrial antibody, Anti nuclear antibody, Anti smooth muscle antibody, F actin IgG, Liver Kidney Microsomal antibody-1, Cytomegalovirus, Epstien-Baar virus, Herpes Simplex virus, Group A streptococcal antigen, Coxsackie virus, Monospot virus and Leptospirosis were negative. Ceruloplasmin and Alpha-1 anti trypsin levels were normal. Human immuno deficiency virus and Rapid plasma reagin tests were negative. Alpha-fetoprotein level was normal at 1 nanogram/milliliter. Iron studies were notable for mild iron deficiency and a Ferritin level of 463 nanogram/milliliter. A comprehensive urine toxicity screen was negative for any drugs except for opiates which he were administered at the hospital for pain management. Liver biopsy done on the 7th day of hospitalization showed acute cholangitis with scant micro vascular fatty changes (less than 5 percent) and no evidence of lobulitis, hepatocytes necrosis, cholestasis, fibrosis, parasite, ova, vasculitis, thrombosis, viral inclusions or neoplasm (Figure-1). Infectious disease consultation was obtained and Vancomycin was added to his antibiotic regimen. No infectious etiology could be determined and patient continued to have hyperbilirubinemia. He was started on Ursodiol 600 mg orally twice a day. His bilirubin level peaked at 18.6 milligram/deciliter, (direct at 10.2) and started to decrease after day 6 of hospitalization. Peak alkaline phosphatase was on day 3 of admission at 298 units/liter and peak AST/ALT levels were 110/142 units/liter respectively on days 11 and 13. All abnormal levels gradually started to decrease (Figure-2). Antibiotics were discontinued after a total 14 days of therapy. Patient was discharged from hospital on day 17 with a bilirubin level of 6.8 milligram/deciliter (direct at 3.2), AST level of 68 units/liter, ALT level of 108 units/liter, alkaline phosphatase level of 160 units/liter. Patient had gradual recovery of liver functions and at 14 weeks after initial onset of symptoms his liver function tests had returned to normal.

Figure 1.

Cholangitis on Liver Biopsy

Figure 2.

Liver Test Results During Hospitalization

Discussion

Use of alternative and herbal medication as dietary supplement is becoming increasing popular in recent years owing to toxicity associated with most prescription medication and the presumed notion of safety with over the counter and so called natural weight loss therapies in the setting of our epidemic of obesity in the United States.

US Congress defined the term “dietary supplement” in the Dietary Supplement Health and Education Act (DSHEA) of 1994.³ A dietary supplement is a product taken by mouth that contains a “dietary ingredient” intended to supplement the diet. The “dietary ingredients” in these products may include: vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites. Dietary supplements can also be extracts or concentrates, and may be found in many forms such as tablets, capsules, soft gels, gel caps, liquids or powders. They can also be in other forms, such as a bar, but if they are, information on their label must not represent the product as a conventional food or a sole item of a meal or diet. Whatever their form may be, DSHEA places dietary supplements in a special category under the general umbrella of “foods,” not drugs, and requires that every supplement be labeled a dietary supplement. Under DSHEA, once the product is marketed, the FDA has the responsibility for showing that a dietary supplement is “unsafe,” before it can take action to restrict the product's use or removal from the marketplace.⁴ In contrast, pharmaceutical companies that produce medications granted approval by the FDA must prove that their products are safe. In other words, with “medications,” the pharmaceutical company must prove their product is safe while in “dietary supplements” it is the FDA's responsibility to prove that the product is unsafe.

Hydroxycut^® was one of the most commonly used dietary supplement is the United States. Hydroxycut^® ingredients include calcium, potassium, chromium and 2 blends known as hydroxagen plus and Hydroxy tea both of which are registered trademarks of Hydroxycut^®. The former blend contains garcinia cambogia rind extract, Gymnema sylvestre leaf extract, Phosphatidylserine-enriched soy Lecithin and rodiola rosea root extract. The latter blend contains green tea leaf extract, anhydrous caffeine, oolong tea extract, ginger root extract, raspberry ketone and quercitine dehydrate.⁵ The key ingredient of Garcinia is Hydroxy Citric Acid (HCA) and there has been a case report of its possible synergistic involvement with montelukast leading to fatal hepatotoxicity.⁶

The patient developed severe liver injury after use of Hydroxycut^® and comprehensive serological and imaging for other causes were negative. The patient needed transport from a community medical center to Hawai‘i Medical Center-East liver transplant center in the event that urgent transplant evaluation would be needed. Fortunately, the patient improved with supportive therapy. He had no other etiologies for possible liver injury. One of the components of Hydroxycut^®, Garcinia, has been associated with both hepatocellular and cholestatic pattern of injury and our biopsy was suggestive of cholangitis likely secondary to infectious or drug mediated injury. Extensive evaluation for infectious disease by an infectious disease specialist failed to diagnose any infection and fevers can be associated with drug induced hepatotoxicity and can last weeks. The authors initially placed the patient on broad spectrum antibiotics while we waited for diagnostic studies to return. He also had severe leukocytosis with a left shift to suggest a bacterial etiology but did not have any significant improvement in jaundice with antibiotics and later gradually improved without them. While causation is difficult to prove in any drug induced injury, the temporal relationship after Hydroxycut^® exposure and gradual improvement after withdrawing the involved medication plus absence of any other etiologies despite comprehensive testing would point to Hydroxycut^® being the most likely possible cause for hepatotoxicity. Earlier reports from Dara et al with case series of 2 patients have shown a similar temporal relationship, also present histological data for possible association with drug toxicity.⁷ A report of 2 cases from Stevens et al showed one with hepatocellular and the other with cholestatic liver toxicity secondary to Hydroxycut^® use.⁸ The latter is more similar to our case reports in terms of presentation, lab values and biopsy report. Shim et al and Jones et al have also reported a case of Hydroxycut^® induced hepatotoxicity each.^9–10 These cases were reviewed by Lobb in a strong case for better post market surveillance and highlighting the significance of case reports in assisting such surveillance.¹¹

Hydroxycut^® was withdrawn by its manufacturer after a May 1, 2009 warning issued by FDA for its possible role in 23 cases of hepatotoxicity.¹²

Conclusion

Obesity continues to be a major health care problem in the Unites States and adult Americans spend over $30 billion a year in weight loss products and services.¹³ Non-conventional products (“natural products”) continue to be touted as “safe and effective” for treatment of various health conditions including weight reduction. However these products have not undergone rigorous scrutiny for effectiveness and safety and consequently drug induced toxicities do occur with some frequency. While some preparations of Hydroxycut^® have been withdrawn form the market by its manufacturer, there still remain a substantial number of similar products on market which may have deleterious health effects. Also it is difficult to convincingly implicate any medication most of the times secondary to polypharmacy and to an extent lack of reporting.

The case also seeks to bring forth the fact that hypersensitivity hepatitis secondary to drugs can also have a superimposed fever, rash and leucocytosis, which may be confused with other viral infections or staphylococcal pharyngitis. Lee has reported similar findings in his review of drug induced hepatotoxicity.¹⁴ Resolution occurs slowly and a high index of suspicion with immediate discontinuation of the offending drug is warranted. The authors hope this case report with temporal and histological evidence of toxicity from Hydroxycut^® in absence of other causes will assist in further defining hepatotoxicity from Hydroxycut^® as well as encourage heath care professionals to be alert to the possibility of severe toxicity from the so called innocuous alternative medications.