Motivation: At some unfortunate moments, you see a person struggling to breathe, and there is not much you can do - even with a tank of oxygen. Hepatopulmonary syndrome (HPS) falls into this category. Short of a liver transplant, no effective medical therapies exist. Multiple vasoconstrictive agents such as somatostatin analogues have been tried without success. After meeting yet another patient with hepatopulmonary syndrome, I was searching for something out of the ordinary when I came across this paper testing the efficacy of garlic (Allium sativum). Seems like it might work.
Paper: De, B.K., Dutta, D., Pal, S.K. et. al. "The role of garlic in hepatopulmonary syndrome: A randomized controlled trial." Can. J. Gastroenterol. (2010), 24: 183-88.
Methods: Randomized controlled trial in a single center (Calcutta Medical College in Kolkata, India). Patients were screened for enrollment if they had portal hypertension. From this cohort, patients were screened for presence of intrapulmonary vascular dilation with elevated A-a gradient. Exclusion criteria included intrinsic cardiopulmonary disease, massive ascites, sepsis, or other severe comorbid condions. The selected patients were randomized to placebo or garlic (at a dose between 1 to 2 g/m2/day based on multiples of 250 mg pills, mean dose 1.55 g/day). Follow-up was 9-18 months. Treatment of primary disease was continued during the trial (antivirals for HBV and HCV and abstinence from alcohol).
Results:
Cohort: Overall, 42 patients were randomized, and 21 patients received either garlic or placebo. In followup, one patient in the placebo group was lost and not analyzed. The mean age of the cohort was about 40 years of age, and majority had alcoholic liver disease followed by chronic Hepatitis B. Majority (at least 85% in both groups) had clubbing on physical exam. Mean PaO2 was 66 in the garlic group and 64 in the placebo group. Mean MELD score was about 15 in both groups.
Efficacy: After nine-months of follow-up, the mean arterial oxygen was higher in the garlic group compared to placebo (83.05 versus 68.75 mmHg, p<0.001). The mean A-a gradient was lower in the garlic group compared to placebo (21.35 vs. 29.11 mmHg, p<0.001). In the garlic group, there was a 24.7% increase in arterial oxygen levels compared to baseline (83.05 versus 66.62 mmHg, p<0.001). Interestingly, in the placebo group, there was also a 7.37% increase in the A-a gradient (68.75 vs. 64.05 mmHg, p = 0.02).
Mortality: In the garlic group, two patients died on follow-up (GI bleed and sepsis). In the placebo group, there were seven deaths (mostly sepsis followed by GI bleed). The mortality, while higher in placebo, did not reach significance (p = 0.052).
Adverse Effects: While no data were presented, authors mentioned that no complications occurred except for "occasional bad breath."
Discussion: This small single center randomized trial suggests that garlic may be efficacious in treating hepatopulmonary syndrome. For a complex mixture like garlic, it is unclear how it acts, but garlic has been speculated to change vascular tone (particularly by NO signaling). Since the patients continued to be treated for primary disease (such as by abstinence from alcohol or by antivirals for HBV or HCV), garlic may alternatively act by potentiating therapy for the primary conditions rather than by treating HPS. In fact, even in the placebo group, the mean PaO2 increased over nine month follow-up indicating that patients getting effective treatment for primary liver condition also had mild subsequent improvement. Given the surprising findings in this small trial (and some smaller previous trials), I was surprised that there has not been a larger trial yet. Part of the difficulty likely lies in the fact that garlic is natural, cheap, and hence unlikely to generate large revenue for a drug manufacturer. Still, a larger trial is very much needed since this current trial suffers from being small, single-center, and likely unblinded to the investigators. For the next patient I meet with HPS, I will think about suggesting garlic!
Paper: De, B.K., Dutta, D., Pal, S.K. et. al. "The role of garlic in hepatopulmonary syndrome: A randomized controlled trial." Can. J. Gastroenterol. (2010), 24: 183-88.
Methods: Randomized controlled trial in a single center (Calcutta Medical College in Kolkata, India). Patients were screened for enrollment if they had portal hypertension. From this cohort, patients were screened for presence of intrapulmonary vascular dilation with elevated A-a gradient. Exclusion criteria included intrinsic cardiopulmonary disease, massive ascites, sepsis, or other severe comorbid condions. The selected patients were randomized to placebo or garlic (at a dose between 1 to 2 g/m2/day based on multiples of 250 mg pills, mean dose 1.55 g/day). Follow-up was 9-18 months. Treatment of primary disease was continued during the trial (antivirals for HBV and HCV and abstinence from alcohol).
Results:
Cohort: Overall, 42 patients were randomized, and 21 patients received either garlic or placebo. In followup, one patient in the placebo group was lost and not analyzed. The mean age of the cohort was about 40 years of age, and majority had alcoholic liver disease followed by chronic Hepatitis B. Majority (at least 85% in both groups) had clubbing on physical exam. Mean PaO2 was 66 in the garlic group and 64 in the placebo group. Mean MELD score was about 15 in both groups.
Efficacy: After nine-months of follow-up, the mean arterial oxygen was higher in the garlic group compared to placebo (83.05 versus 68.75 mmHg, p<0.001). The mean A-a gradient was lower in the garlic group compared to placebo (21.35 vs. 29.11 mmHg, p<0.001). In the garlic group, there was a 24.7% increase in arterial oxygen levels compared to baseline (83.05 versus 66.62 mmHg, p<0.001). Interestingly, in the placebo group, there was also a 7.37% increase in the A-a gradient (68.75 vs. 64.05 mmHg, p = 0.02).
Mortality: In the garlic group, two patients died on follow-up (GI bleed and sepsis). In the placebo group, there were seven deaths (mostly sepsis followed by GI bleed). The mortality, while higher in placebo, did not reach significance (p = 0.052).
Adverse Effects: While no data were presented, authors mentioned that no complications occurred except for "occasional bad breath."
Discussion: This small single center randomized trial suggests that garlic may be efficacious in treating hepatopulmonary syndrome. For a complex mixture like garlic, it is unclear how it acts, but garlic has been speculated to change vascular tone (particularly by NO signaling). Since the patients continued to be treated for primary disease (such as by abstinence from alcohol or by antivirals for HBV or HCV), garlic may alternatively act by potentiating therapy for the primary conditions rather than by treating HPS. In fact, even in the placebo group, the mean PaO2 increased over nine month follow-up indicating that patients getting effective treatment for primary liver condition also had mild subsequent improvement. Given the surprising findings in this small trial (and some smaller previous trials), I was surprised that there has not been a larger trial yet. Part of the difficulty likely lies in the fact that garlic is natural, cheap, and hence unlikely to generate large revenue for a drug manufacturer. Still, a larger trial is very much needed since this current trial suffers from being small, single-center, and likely unblinded to the investigators. For the next patient I meet with HPS, I will think about suggesting garlic!
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