Data were collected and analyzed for the 275 patients with portal hypertension without intrinsic cardiopulmonary disease, of whom 60 had evidence of IPVDs indicated by a positive CEE. Of these 60 patients, 48 (17.45% of the 275 patients) had an increased alveolar-arterial difference for the partial pressure of oxygen above the age-related threshold and were diagnosed with HPS (group A). Twelve patients (4.36% of the 275 patients) had evidence of IVPD, with a normal alveolar-arterial difference for the partial pressure of oxygen for their age and were diagnosed with incomplete syndrome (IS) (group B). The remaining 215 patients who had no evidence of IPVD were classified as group C. The study design and follow-up is elaborated in .
Summary of trial design and follow-up. ABG Arterial blood gas; P(A-a)O2 Alveolar-arterial oxygen gradient
Cyanosis, clubbing and spider angioma were present in 38 (79.16%), 42 (87.5%) and 11 (22.72%) patients with HPS, respectively, compared with only two (16.67%), two (16.67%) and one (8.33%) patient(s) with IS. Orthodeoxia was significantly higher in patients with HPS (31 of 48 patients [64.58%]) than in those with IS (three of 12 patients [25%]; P=0.01). Orthodeoxia was present in five of six patients with HPS due to Budd-Chiari syndrome. Twenty-six of the 42 patients with HPS who were randomly assigned to receive garlic or placebo had orthodeoxia.
A conservative estimate of disease duration was made based on the date the patient became aware of his or her illness to the date they entered the study. The duration of liver disease was significantly longer among patients with HPS (12.73±6.56 years) and IS (11.8±9.69 years) than in group C (8.66±7.32 years; P=0.002). Model for End-stage Liver Disease (MELD) score was higher in patients with HPS (15.98±6.18) than in those with IS (14.45±4.3), but not statistically significant (P=0.56). The MELD score of the patients in group C was only marginally lower (13.07±5.61).
Of the 48 patients in group A, six patients had HPS due to Budd-Chiari syndrome and were treated with cavoplasty and stent placement and were consequently excluded. The remaining 42 patients were divided into two groups by computer-generated randomized table, 21 patients in group 1 (patients receiving garlic) and 21 patients in group 2 (patients receiving placebo). One patient in group 2 did not return for follow-up. Therefore, 41 patients (21 patients in group 1 and 20 patients in group 2) were analyzed for the effects of garlic versus placebo. There were no significant differences in the baseline clinical, biochemical or blood gas profile of patients with HPS in group 1 or group 2 (). The mean dose of garlic taken by patients in group 1 was 1.55±0.29 g/day.
Baseline clinical, biochemical and arterial blood gas profiles of patients with hepatopulmonary syndrome taking garlic (group 1) or placebo (group 2)
The total duration of follow-up ranged from a minimum of nine months to a maximum of 18 months. No serious adverse effects were documented in either of the groups.
There was a 24.66% increase in baseline arterial oxygen levels (83.05 mmHg versus 66.62 mmHg; P<0.001) after nine months of follow-up in patients with HPS who received garlic. In contrast, only a 7.37% increase (68.75 mmHg versus 64.05 mmHg; P=0.02) was observed in individuals in the placebo group. In addition, there was a 28.35% decrease in alveolar-arterial oxygen gradient (21.35 mmHg versus 29.77 mmHg; P<0.001) after nine months of follow-up among patients with HPS receiving garlic, in contrast to a 10.73% decrease (29.11 mmHg versus 32.61 mmHg; P=0.12) among those in the placebo group. The arterial oxygen level was significantly higher in patients receiving garlic compared with those receiving placebo after nine months of follow-up (83.05 mmHg versus 68.75 mmHg; P<0.001). Also, the alveolar-arterial oxygen gradient was significantly lower in patients receiving garlic compared with those receiving placebo after nine months (21.35 mmHg versus 29.11 mmHg; P<0.001). summarizes the clinical and arterial blood gas profiles of patients on garlic or placebo during follow-up.
Evolution of clinical and arterial blood gas profile of patients with hepatopulmonary syndrome on garlic supplementation (group 1) or placebo (group 2) during follow-up (n=41)
In group 1, 10 patients became HPS negative (ie, responder) three months after commencement of oral garlic therapy, two patients after six months and three patients became responders after nine months of garlic supplementation. The reversal of CEE was associated with the reversal of cyanosis, spider angioma and clubbing (). One of the responders to garlic supplementation died after three months of follow-up, following an episode of massive upper gastrointestinal bleeding. Another patient in group 1, in whom HPS did not reverse, died after 15 months of follow-up, following chronic hepatic encephalopathy and sepsis that did not respond to conservative management.
Among the patients in group 2 (placebo), one patient had reversal of HPS (responder) after six months of follow-up. In the remaining patients, in spite of the persistence of IVPD indicated by a positive CEE, there was a progressive, albeit mild improvement in arterial oxygen saturation, with a reduction in the alveolar-arterial oxygen gradient (). The incidence of complications was much higher among patients in group 2 (placebo) than among those in group 1 (garlic). Of the patients in group 2, two died within three months of follow-up, one due to sepsis complicated by hepatorenal syndrome, the other from gastrointestinal bleeding. Another patient died after six months of follow-up, following sepsis-associated encephalopathy. One more patient was lost due to spontaneous bacterial peritonitis and hepatorenal syndrome after eight months of follow-up. Of the three patients who completed 12 months of follow-up, one died at home (the cause of which could not be ascertained), another died following an episode of variceal bleeding and the third patient died after 15 months of follow-up, following sepsis associated with nonhealing pressure sores. The mortality was higher among patients in group 2 (P=0.052 [log rank test]), as illustrated by the Kaplan-Meier plot (), and approached statistical significance.
Kaplan-Meier survival curve of patients with hepatopulmonary syndrome on garlic (group 1) or placebo (group 2). NS Not statistically significant