Comparison of Arterial vs Venous Ammonia Levels in Hepatic Encephalopathy

INTRODUCTION

Hepatic encephalopathy is defined as a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction, after exclusion of brain disease.^1–3 Hepatic encephalopathy is characterized by personality changes, intellectual impairment, and a depressed level of consciousness.⁴ An important prerequisite for the syndrome is diversion of portal blood into the systemic circulation through portosystemic collateral vessels.⁵ Subtle signs of hepatic encephalopathy are observed in nearly 70% of patients with cirrhosis.

Cirrhosis is the final stage of chronic liver disease which results in distortion of the hepatic architecture by fibrosis and the formation of regenerativenodules.⁶ It is the result of progressive liver fibrosis caused by chronic liver diseases, including viral hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, autoimmune liver disease, and genetic disorders, among others. Alcohol emerged as the most common etiology of cirrhosis, while hepatitis B virus (HBV) was the commonest cause in the noncirrhotic chronic liver disease.

A number of theories have been proposed to explain the development of hepatic encephalopathy in patients with cirrhosis. Some investigators contend that hepatic encephalopathy is a disorder of astrocyte function as they also play a role in the detoxification of a number of chemicals, including ammonia.

It is theorized that neurotoxic substances, including ammonia and manganese, may gain entry into the brain in the setting of liver failure. These neurotoxic substances may then contribute to morphologic changes in astrocytes. In cirrhosis, astrocytes may undergo astrocytosis, and astrocytes become swollen. They may develop a large pale nucleus, a prominent nucleolus, and margination of chromatin. Arterial levels best prognosticate circulating ammonia, correlating to hepatic encephalopathy severity.⁷ In acute liver failure and cirrhosis, arterial ammonia levels of >150 μmol/L predict a poor outcome⁶ and correlate with increased intracranial pressure (ICP) and cerebral edema. This may lead to increased intracranial pressure and, potentially, brain herniation.⁸

Therefore, ammonia levels both help in diagnosis and serve as a guide in treatment. Diagnosis of hepatic encephalopathy can be done based on clinical criteria, and the severity of hepatic encephalopathy can be graded by West Haven criteria which is as follows:⁹

• Grade I—Trivial lack of awareness; shortened attention span; impaired addition or subtraction; hypersomnia, insomnia, or inversion of sleep pattern; euphoria, depression, or irritability; mild confusion; slowing of ability to perform mental tasks
• Grade II—Lethargy or apathy; disorientation; inappropriate behavior; slurred speech; obvious asterixis; drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, and intermittent disorientation, usually regarding time
• Grade III—Somnolent but can be aroused; unable to perform mental tasks; disorientation about time and place; marked confusion; amnesia; occasional fits of rage; present but incomprehensible speech
• Grade IV—Coma with or without response to painful stimuli.

This study was done to correlate arterial and venous ammonia levels in hepatic encephalopathy and to correlate arterial and venous ammonia levels with the severity of hepatic encephalopathy. This study was never done before in this college and was undertaken with the above-mentioned objectives.

MATERIALS AND METHODS

The present study was an observational study which was conducted after clearance from ethical committee in 60 patients of hepatic encephalopathy admitted to emergency ward/intensive care unit of Sri Guru Ram Das Institute of Medical Sciences and Research, Vallah, Amritsar. All the patients were apprised of the study to be carried out on them and their written informed consent were obtained and recorded on the consent form. A complete clinical examination of patients was done. The patient were screened for liver function tests, renal function tests, complete blood count, prothrombin time, ammonia levels both arterial and venous and other routine investigations.

RESULTS

This study was conducted on 60 patients of hepatic encephalopathy with maximum number of patients in the age group of 51–60 years of age constituting 36.7% patients (n = 22, of which 19 were males and 3 were females; Fig. 1).

Of the total of 60 patients, 85% patients (n = 51) were males and 15% patients (n = 9) were females (Fig. 2).

On the basis of etiology, most of the patients were found to be alcoholics followed by hepatitis C positive.

On day 1 of admission, 33.3% of the patients (n = 20) had grade I, 26.7% of patients (n = 16) had grade II, 25.0% of patients (n = 15) had grade III, and 15.0% of patients (n = 9) had grade IV. On day 3 of admission (patients started on treatment), 41.7% of the patients (n = 25) had grade I, 38.3% of patients (n = 23) had grade II, 18.3% of patients (n = 11) had grade III, and 1.7% of patients (n = 1) had grade IV. On day 5 of admission, number of patients in grade I increased to 76.7% of the patients (n = 46) and may be due to effect of the treatment given during hospital stay, 16.7% of patients (n = 10) had grade II, 5.0% of patients (n = 3) had grade III, 1.7% of patients (n = 1) had grade IV (Figs 3 to 5).

Arterial ammonia levels on days 1, 3 and 5 of admission were measured and correlated with West Haven grading of hepatic encephalopathy. Arterial ammonia levels increased with increasing severity of hepatic encephalopathy, i.e., p value %3C; 0.001 (Fig. 6 and Table 1).

However, venous ammonia levels on days 1, 3, and 5 of admission were also measured and correlated with the severity of hepatic encephalopathy, and it was observed that venous ammonia levels do increase in patients of hepatic encephalopathy, but the increase in its levels does not correlate statistically with increasing severity of hepatic encephalopathy with p values %3E;0.05 (i.e., nonsignificant) (Fig. 7 and Table 2).

Various other laboratory parameters were also correlated with grades of hepatic encephalopathy like serum albumin levels, blood urea nitrogen, serum creatinine, serum bilirubin, and other parameters of liver function tests.

DISCUSSION

Hepatic encephalopathy is a reversible neuropsychiatric state that complicates liver disease. Pathogenesis of hepatic encephalopathy in chronic liver dysfunction is widely accepted to be due to failure of hepatic clearance of toxic products from gut. Exact toxin involved remains controversial, but ammonia is strongly considered as a central factor in the pathogenesis of hepatic encephalopathy.^10–12

The present study was a prospective clinical study consisting of 60 patients admitted to Department of Medicine, Sri Guru Ram Das Institute of Medical Sciences and Research, who were diagnosed to have hepatic encephalopathy. After taking the informed consent, relevant history, and detailed clinical examination, arterial and venous ammonia levels were done on days 1, 3, and 5. It was done to correlate whether serum ammonia levels increase with increasing severity of hepatic encephalopathy and to find out whether arterial ammonia measurements are a better indicator of hepatic encephalopathy when compared with venous ammonia levels.

In the our study, the severity of hepatic encephalopathy was assessed by West Haven grading system, and it was observed that serum total ammonia levels increased with the severity of hepatic encephalopathy. It was found that increase in arterial ammonia levels correlated statistically with increasing severity of hepatic encephalopathy. Venous ammonia levels had also increased, but the increase was not statistically significant. These suggested that ammonia levels definitely play an important role in the pathogenesis of hepatic encephalopathy and also suggested that arterial ammonia measurements are superior to venous ammonia while assessing the severity of hepatic encephalopathy. In the present study, it was also observed that increased ammonia levels correlated with the severity of hepatic encephalopathy, and highest levels were seen in grades III and IV. This correlated with the study done by Janus et al. where maximum arterial ammonia levels were seen in grades III and IV of the West Haven grading.

Stahl et al.¹³ in his study had found that estimation of arterial ammonia in drowsy with suspected liver failure was of diagnostic significance.

In the study done by Nicolao et al.,¹⁴ it was observed that highest ammonia levels were seen in grades III and IV hepatic encephalopathy groups.

In the present study, it was also observed that serum albumin levels correlated inversely with the severity of hepatic encephalopathy as albumin levels were found to be 2.4 ± 0.75 in grade I, 2.28 ± 0.41 in grade II, 2.18 ± 0.04 in grade III, and 2.13 ± 0.35 in grade IV, but the results were not statistically significant. It was also observed that serum creatinine increased with the severity of hepatic encephalopathy, and the results were statistically significant. The results of our study were consistent with the results of study done by Manjunath et al.,¹⁵ where serum albumin levels statistically correlated inversely with the severity of hepatic encephalopathy.

In the present study, it was observed that even prothrombin index (PTI) decreased with the severity of hepatic encephalopathy; this correlation was statistically significant. Our study was supported by the study of Ong et al.,¹⁶ where it was observed that prothrombin time statistically increased with the severity of hepatic encephalopathy with the p value <0.005. In a study by Manjunath et al., it was observed that even though prothrombin time increased with the severity of hepatic encephalopathy, this correlation was not statistically significant.

In the present study, it was observed that highest incidence of hepatic encephalopathy was seen with the age group 51–60 years, 36.7% (n = 22), and 41–50 years, 28.3% (n = 17), in males and 51–60 years, 37.5% (n = 3), in the females. There was no significant age difference of the mean age between male and female patients. These results were in correlation with the other studies done by Kumar et al.¹⁷ (mean age 44.5 ± 6.7 years), Chakrabarti et al.¹⁸ (mean age 49.8 ± 12.9 years), Nandakumar et al.¹⁹ (mean age 47.5 ± 8.7 years), and Janus et al. (mean age 54 ± 10 years). In these studies, also incidence of hepatic encephalopathy in chronic liver disease was more common in the age group 41–60 years.

In the present study, it was found that the most common presenting symptoms were altered sensorium (41.7%, n = 25), distention of abdomen, i.e., ascitis (18.3%, n = 11), jaundice (15%, n = 9), swelling of the feet (11.7%, n = 7), hematemesis (10%, n = 6), and malena (3.3%, n = 2). These results were similar to the results seen in the studies done by Manjunath et al., where altered sensorium was the most common presenting symptom with 96% (n = 48), ascitis in 72% (n = 36), icterus in 70% (n = 35), edema in 60% (n = 30), hematemesis in 6% (n = 3), and melena in 6% (n = 3) patients. A study by Tandon et al. where patients of cirrhosis with hepatic encephalopathy had presented with similar symptoms.

In the present study, it was observed that serum creatinine values increased with increased grades of hepatic encephalopathy, and this correlation was statistically significant. In cirrhosis, the diagnosis of renal failure is defined as a serum creatinine level of more than 1.5 μg/dL, which corresponds to a glomerular filtration rate of approximately 30 mL/minute. Elevation in serum creatinine is a common laboratory finding for patients with cirrhosis and can indicate the presence of either an acute kidney injury or chronic kidney disease.²⁰

CONCLUSION

The conclusions of our study are as follows:

Incidence of hepatic encephalopathy was more in males than females.

• Majority of patient were in grade I as assessed by West Haven grading on days 1, 3, and 5 of admission. Both arterial and venous ammonia levels increase in patients of hepatic encephalopathy, but the arterial ammonia levels correlated better with the severity of hepatic encephalopathy when compared with the venous ammonia levels.
• Other parameters like serum creatinine and prothrombin time also correlated with the severity of hepatic encephalopathy as creatinine levels increased with increasing severity of hepatic encephalopathy and PTI decreased with increasing severity of hepatic encephalopathy.
• Serum albumin correlated inversely with the severity of hepatic encephalopathy.

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