clinical obesity
doi: 10.1111/cob.12075
Case Report
Orlistat-induced fulminant hepatic failure D. Sall1, J. Wang2, M. Rashkin1, M. Welch3, C. Droege3 and D. Schauer1
1
Department of Internal Medicine, University
of Cincinnati Medical Center, Cincinnati, OH, USA; 2Department of Pathology, University of Cincinnati Medical Center, Cincinnati, OH, USA; 3Department of Pharmacy Services, University of Cincinnati Medical Center, Cincinnati, OH, USA
Received 26 May 2014; revised 6 August 2014; accepted 11 August 2014
Address for correspondence: Dr D Sall, Department of Internal Medicine, University of Cincinnati, 234 Goodman Street, Cincinnati, OH 45219, USA. E-mail: [email protected]
Summary Orlistat was approved by the Food and Drug Administration in 1998 and has been shown to be superior to placebo in achieving weight loss. It is generally well tolerated. However, severe liver injury has been reported. We present a case of hepatic failure in a patient taking orlistat. A 54-year-old African-American woman with hypertension presented with hepatic failure. She had noticed increasing fatigue, jaundice and confusion. She used alcohol sparingly and denied tobacco or illicit drug use, but had been taking over-the-counter orlistat for the past two months. Physical examination revealed scleral icterus, jaundice, asterixis and slow speech. Laboratory testing showed markedly abnormal liver function tests with coagulopathy. Acute viral and autoimmune serologies were negative, as was toxicology screen. Liver biopsy showed necrotic hepatic parenchyma likely secondary to drug toxicity. Based upon her clinical presentation and time course, the pattern of liver injury seen on liver biopsy and lack of an alternative plausible explanation, her liver failure was most likely associated with orlistat use. She continued to deteriorate and ultimately underwent orthotopic liver transplantation. Fourteen cases of severe liver injury associated with orlistat use have been reported, four of which are detailed in the literature. This is the second published case of liver failure associated with over-the-counter orlistat usage. Clinicians should be aware of the growing number of cases associating liver injury and orlistat use and carefully monitor their patients on this medication for signs of hepatic dysfunction. Keywords: Hepatic failure, liver transplant, orlistat.
Introduction Over the past 30 years, rates of obesity have doubled in US adults (1). The World Health Organization estimates that over 400 million adults are obese and an additional 1.6 billion are overweight (2). Obesity has been implicated in many chronic conditions, including cardiovascular disease, diabetes mellitus, hypertension, obstructive sleep apnoea, hyperlipidaemia, fatty liver disease and malignancy (2,3), and is the leading cause of mortality in the United States (1). Achieving weight loss of 5–10% of baseline body weight has been shown to improve many of these 342
co-morbid conditions (1,2). Despite the high prevalence of overweight patients, physicians often feel unsuccessful in weight loss management (4). Orlistat was approved by the Food and Drug Administration (FDA) in 1998 for weight loss. It is a pancreatic and gastric lipase inhibitor, resulting in a 30% reduction in fat absorption. Clinical guidelines recommend that orlistat be used for adults with a body mass index (BMI) of 30 kg m−2 or more, or in adults with a BMI of 28 kg m−2 or more with obesity-associated conditions (1). Orlistat exists as a prescription medication (120 mg, three times daily) and an over-the-counter preparation (60 mg, three times daily). © 2014 The Authors Clinical Obesity © 2014 World Obesity. clinical obesity 4, 342–347
clinical obesity
Orlistat and hepatic failure D. Sall et al.
Table 1 Presenting liver function tests and coagulation panel Liver function panel
Coagulation panel
Published data have shown orlistat to be superior to placebo in achieving weight loss (1–3,5–7). The XENDOS study, which compared orlistat to placebo in over 3000 patients, showed statistically significant and sustained weight loss at the end of a 4-year study period (5.8 and 3.0 kg, respectively) (7). Orlistat has also been shown to decrease total cholesterol and low-density lipoprotein levels independent of weight loss (5). It has also been shown to decrease the incidence of diabetes in patients with impaired fasting glucose and to reduce blood pressure (6). Lastly, orlistat has been shown to decrease serum aminotransferases (8,9) and improve ultrasonic appearance of the liver in patients with non-alcoholic fatty liver disease (NAFLD) independent of the level of weight loss (9). Some studies have even shown improvement of liver histology of biopsy-proven NAFLD after orlistat use (10,11), although these studies were small and the results were not universal (8,11). Orlistat is generally well tolerated. Adverse effects are mild and include dyspepsia, faecal incontinence, bloating and steatorrhoea. These side effects dissipate with continued medication usage (2,3). Other reported adverse effects include cutaneous vasculitis, acute kidney injury secondary to crystal nephropathy and liver injury (12). We add to the small number of case reports by presenting the second published case in the United States of orlistatinduced fulminant hepatic failure in a patient taking overthe-counter orlistat.
Case A 54-year-old African-American female dialysis nurse presented to the intensive care unit with fulminant hepatic failure. Past history was significant for hypertension and a hysterectomy. She denied any personal or family history of liver or autoimmune disease. Chronic medications included lisinopril and oestrogen replacement therapy. For 3 weeks, she had noticed increasing fatigue, generalized weakness, nausea and progressive jaundice with pruritus. She endorsed darker urine and clay-coloured stools for the last © 2014 The Authors Clinical Obesity © 2014 World Obesity. clinical obesity 4, 342–347
343
Laboratory parameter
Patient value
Reference range
Alkaline phosphatase Aspartate aminotransferase Alanine aminotransferase Total bilirubin Direct bilirubin Albumin Total protein Prothrombin time Partial thromboplastin time International normalized ratio
398 2195 1942 19.2 12.3 3.3 7.4 39.6 54.5 3
33–130 U L−1 14–36 U L−1 6–40 U L−1 0.2–1.2 mg dL−1 0.0–0.2 mg dL−1 3.6–5.1 g dL−1 6.2–8.3 g dL−1 11.6–14.4 s 24.3–33.1 s 0.9–1.1
week. She denied abdominal pain, constipation, diarrhoea, melena or haematochezia. She had noticed increasing confusion and word-finding difficulties. She denied fevers, night sweats, sick contacts or recent travel. She used the city water supply and denied use of herbal supplements or acetaminophen. She denied tobacco or illicit drug use and used alcohol sparingly. Of note, she had been taking overthe-counter orlistat for the two months prior to admission. Orlistat was taken as directed, 60 mg by mouth three times daily with meals. One week prior to admission, she stopped taking orlistat as a result of these symptoms. On presentation, the patient was afebrile with normal vital signs. She was overweight with a BMI of 28.1 kg m−2 (weight 184.97 lb, height 5′8″). Physical examination was significant for scleral icterus, jaundice and asterixis. There were no stigmata of chronic liver disease or ascites. Neurologically, she was fully oriented, but displayed slow speech and had word-finding difficulties. Laboratory testing revealed markedly abnormal liver function tests with significant coagulopathy, a complete list of which can be found in Table 1. Complete blood count and basic metabolic panels were unremarkable. Acute viral serologies and autoimmune work-up were negative. Urinary toxicology screen was negative. Acetaminophen and ethanol levels were less than 10 mg L−2. Complete laboratory values can be found in Tables 2–4. Abdominal ultrasound with Doppler showed the liver to be diffusely heterogenous in echogenicity with pulsatile flow within the main portal vein, likely secondary to the acute liver failure. Hepatology was consulted and the patient was managed supportively. The patient underwent liver biopsy on hospital day 3 (Fig. 1), which showed entirely necrotic hepatic parenchyma. Iron, copper and PAS-D stains were negative. The pathology report named drug toxicity as the most likely mechanism for liver injury. The pharmacists involved in the case then submitted a report to MedWatch, the FDA Safety Information and Adverse Event Reporting Program, detailing the fulminant hepatic failure the patient experienced after taking orlistat. Additional details were provided to an
clinical obesity
344 Orlistat and hepatic failure D. Sall et al.
Viral studies
Autoimmune serologies/ Acute liver failure work-up
Laboratory parameter
Patient value
Reference range
CMV IgM CMV IgG CMV, DNA, quantitative EBV IgM EBV IgG EBV DNA, quantitative HSV 1, PCR HSV 2, PCR Hep A IgM Hep A IgG Hep B surface Ab Hep B surface antigen Hep B core IgM Hep B core total Ab Hep B E antigen Hep C antibody Hep C RNA, quantitative Hep E IgM HIV Antinuclear antibody Anti-mitochondrial antibody Anti-smooth muscle antibody Ceruloplasmin Alpha-1 antitrypsin
Negative Positive 0 Negative Positive 0 Negative Negative Negative Positive Positive Negative Negative Negative Negative Negative Not detected Negative Negative Negative
doi: 10.1111/cob.12075
Case Report
Orlistat-induced fulminant hepatic failure D. Sall1, J. Wang2, M. Rashkin1, M. Welch3, C. Droege3 and D. Schauer1
1
Department of Internal Medicine, University
of Cincinnati Medical Center, Cincinnati, OH, USA; 2Department of Pathology, University of Cincinnati Medical Center, Cincinnati, OH, USA; 3Department of Pharmacy Services, University of Cincinnati Medical Center, Cincinnati, OH, USA
Received 26 May 2014; revised 6 August 2014; accepted 11 August 2014
Address for correspondence: Dr D Sall, Department of Internal Medicine, University of Cincinnati, 234 Goodman Street, Cincinnati, OH 45219, USA. E-mail: [email protected]
Summary Orlistat was approved by the Food and Drug Administration in 1998 and has been shown to be superior to placebo in achieving weight loss. It is generally well tolerated. However, severe liver injury has been reported. We present a case of hepatic failure in a patient taking orlistat. A 54-year-old African-American woman with hypertension presented with hepatic failure. She had noticed increasing fatigue, jaundice and confusion. She used alcohol sparingly and denied tobacco or illicit drug use, but had been taking over-the-counter orlistat for the past two months. Physical examination revealed scleral icterus, jaundice, asterixis and slow speech. Laboratory testing showed markedly abnormal liver function tests with coagulopathy. Acute viral and autoimmune serologies were negative, as was toxicology screen. Liver biopsy showed necrotic hepatic parenchyma likely secondary to drug toxicity. Based upon her clinical presentation and time course, the pattern of liver injury seen on liver biopsy and lack of an alternative plausible explanation, her liver failure was most likely associated with orlistat use. She continued to deteriorate and ultimately underwent orthotopic liver transplantation. Fourteen cases of severe liver injury associated with orlistat use have been reported, four of which are detailed in the literature. This is the second published case of liver failure associated with over-the-counter orlistat usage. Clinicians should be aware of the growing number of cases associating liver injury and orlistat use and carefully monitor their patients on this medication for signs of hepatic dysfunction. Keywords: Hepatic failure, liver transplant, orlistat.
Introduction Over the past 30 years, rates of obesity have doubled in US adults (1). The World Health Organization estimates that over 400 million adults are obese and an additional 1.6 billion are overweight (2). Obesity has been implicated in many chronic conditions, including cardiovascular disease, diabetes mellitus, hypertension, obstructive sleep apnoea, hyperlipidaemia, fatty liver disease and malignancy (2,3), and is the leading cause of mortality in the United States (1). Achieving weight loss of 5–10% of baseline body weight has been shown to improve many of these 342
co-morbid conditions (1,2). Despite the high prevalence of overweight patients, physicians often feel unsuccessful in weight loss management (4). Orlistat was approved by the Food and Drug Administration (FDA) in 1998 for weight loss. It is a pancreatic and gastric lipase inhibitor, resulting in a 30% reduction in fat absorption. Clinical guidelines recommend that orlistat be used for adults with a body mass index (BMI) of 30 kg m−2 or more, or in adults with a BMI of 28 kg m−2 or more with obesity-associated conditions (1). Orlistat exists as a prescription medication (120 mg, three times daily) and an over-the-counter preparation (60 mg, three times daily). © 2014 The Authors Clinical Obesity © 2014 World Obesity. clinical obesity 4, 342–347
clinical obesity
Orlistat and hepatic failure D. Sall et al.
Table 1 Presenting liver function tests and coagulation panel Liver function panel
Coagulation panel
Published data have shown orlistat to be superior to placebo in achieving weight loss (1–3,5–7). The XENDOS study, which compared orlistat to placebo in over 3000 patients, showed statistically significant and sustained weight loss at the end of a 4-year study period (5.8 and 3.0 kg, respectively) (7). Orlistat has also been shown to decrease total cholesterol and low-density lipoprotein levels independent of weight loss (5). It has also been shown to decrease the incidence of diabetes in patients with impaired fasting glucose and to reduce blood pressure (6). Lastly, orlistat has been shown to decrease serum aminotransferases (8,9) and improve ultrasonic appearance of the liver in patients with non-alcoholic fatty liver disease (NAFLD) independent of the level of weight loss (9). Some studies have even shown improvement of liver histology of biopsy-proven NAFLD after orlistat use (10,11), although these studies were small and the results were not universal (8,11). Orlistat is generally well tolerated. Adverse effects are mild and include dyspepsia, faecal incontinence, bloating and steatorrhoea. These side effects dissipate with continued medication usage (2,3). Other reported adverse effects include cutaneous vasculitis, acute kidney injury secondary to crystal nephropathy and liver injury (12). We add to the small number of case reports by presenting the second published case in the United States of orlistatinduced fulminant hepatic failure in a patient taking overthe-counter orlistat.
Case A 54-year-old African-American female dialysis nurse presented to the intensive care unit with fulminant hepatic failure. Past history was significant for hypertension and a hysterectomy. She denied any personal or family history of liver or autoimmune disease. Chronic medications included lisinopril and oestrogen replacement therapy. For 3 weeks, she had noticed increasing fatigue, generalized weakness, nausea and progressive jaundice with pruritus. She endorsed darker urine and clay-coloured stools for the last © 2014 The Authors Clinical Obesity © 2014 World Obesity. clinical obesity 4, 342–347
343
Laboratory parameter
Patient value
Reference range
Alkaline phosphatase Aspartate aminotransferase Alanine aminotransferase Total bilirubin Direct bilirubin Albumin Total protein Prothrombin time Partial thromboplastin time International normalized ratio
398 2195 1942 19.2 12.3 3.3 7.4 39.6 54.5 3
33–130 U L−1 14–36 U L−1 6–40 U L−1 0.2–1.2 mg dL−1 0.0–0.2 mg dL−1 3.6–5.1 g dL−1 6.2–8.3 g dL−1 11.6–14.4 s 24.3–33.1 s 0.9–1.1
week. She denied abdominal pain, constipation, diarrhoea, melena or haematochezia. She had noticed increasing confusion and word-finding difficulties. She denied fevers, night sweats, sick contacts or recent travel. She used the city water supply and denied use of herbal supplements or acetaminophen. She denied tobacco or illicit drug use and used alcohol sparingly. Of note, she had been taking overthe-counter orlistat for the two months prior to admission. Orlistat was taken as directed, 60 mg by mouth three times daily with meals. One week prior to admission, she stopped taking orlistat as a result of these symptoms. On presentation, the patient was afebrile with normal vital signs. She was overweight with a BMI of 28.1 kg m−2 (weight 184.97 lb, height 5′8″). Physical examination was significant for scleral icterus, jaundice and asterixis. There were no stigmata of chronic liver disease or ascites. Neurologically, she was fully oriented, but displayed slow speech and had word-finding difficulties. Laboratory testing revealed markedly abnormal liver function tests with significant coagulopathy, a complete list of which can be found in Table 1. Complete blood count and basic metabolic panels were unremarkable. Acute viral serologies and autoimmune work-up were negative. Urinary toxicology screen was negative. Acetaminophen and ethanol levels were less than 10 mg L−2. Complete laboratory values can be found in Tables 2–4. Abdominal ultrasound with Doppler showed the liver to be diffusely heterogenous in echogenicity with pulsatile flow within the main portal vein, likely secondary to the acute liver failure. Hepatology was consulted and the patient was managed supportively. The patient underwent liver biopsy on hospital day 3 (Fig. 1), which showed entirely necrotic hepatic parenchyma. Iron, copper and PAS-D stains were negative. The pathology report named drug toxicity as the most likely mechanism for liver injury. The pharmacists involved in the case then submitted a report to MedWatch, the FDA Safety Information and Adverse Event Reporting Program, detailing the fulminant hepatic failure the patient experienced after taking orlistat. Additional details were provided to an
clinical obesity
344 Orlistat and hepatic failure D. Sall et al.
Viral studies
Autoimmune serologies/ Acute liver failure work-up
Laboratory parameter
Patient value
Reference range
CMV IgM CMV IgG CMV, DNA, quantitative EBV IgM EBV IgG EBV DNA, quantitative HSV 1, PCR HSV 2, PCR Hep A IgM Hep A IgG Hep B surface Ab Hep B surface antigen Hep B core IgM Hep B core total Ab Hep B E antigen Hep C antibody Hep C RNA, quantitative Hep E IgM HIV Antinuclear antibody Anti-mitochondrial antibody Anti-smooth muscle antibody Ceruloplasmin Alpha-1 antitrypsin
Negative Positive 0 Negative Positive 0 Negative Negative Negative Positive Positive Negative Negative Negative Negative Negative Not detected Negative Negative Negative
