There are many groups of patients that alter how we must evaluate and interpret our diagnostic studies in the setting of baseline chronic laboratory abnormalities, which is often challenging. One especially challenging patient population are patients with chronic liver disease, and in this post we will look into how their disease process create chronic and acute on chronic derangements of which we need to be aware.
Why is this a “special” patient population?
In 2010, more than 1 million deaths and > 31 million disability adjusted life years (DALYs) were due to liver cirrhosis (1). In the US, chronic hepatitis C infection is the leading indicated for liver transplantation, with alcoholic liver disease coming in second. (2). Cirrhosis disproportional affects men and women in their working years and certain ethnic minorities, especially Native Americans, Hispanic Americans, and African Americans as compared to non-Hispanic white Americans. Risk factors include low socioeconomic status, alcohol use, hepatitis, drug use, environmental and industrial toxins, and genetic predisposition. Increased risk observed for unmarried individuals, urban residents, unemployed, and those with lower educational attainment and family income (3). This is also a group that frequently utilizes health care resources, including the emergency department, and accrues substantial health care-related costs (4,5). Liver disease account for $1.2 trillion in US healthcare expenditures (6). Additionally, hepatic encephalopathy, when all grades are considered, affects up to 80% of cirrhotic patients and these patients are at increased risk for MVCs (7).
Scoring of Liver Failure
These scoring systems use serum markers of liver synthetic function (INR), metabolism (bilirubin), and end organ function (creatinine, sodium, dialysis, ascites, hepatic encephalopathy) to risk stratify patients. The Child-Pugh Score and MELD (and later the MELD-Na score) are use to prioritize patients for liver transplantation. They have also demonstrated prognostic implications for patients as well, as patients with higher scores have more degree of liver and end organ dysfunction.
The CLIF-SOFA score is a modified scoring system, based on the SOFA score, that was developed to classify acute on chronic liver failure and to predict mortality in these patients. The CLIF-SOFA evaluates liver (bilirubin), kidney (creatinine), cerebral (HE grade), coagulation (INR), circulation (MAP), and lung (PaO2/FiO2 or SpO2/FiO2) function. It incorporates evaluation of liver dysfunction and replaces indices for end organ dysfunction with measures that are specific to patients with liver dysfunction, i.e. HE grade rather GCS for evaluation of cerebral function and INR rather than platelets to evaluate coagulation function. Higher CLIF-SOFA scores are predictive of poor prognosis (10,11). CLIF-SOFA was shown to be superior to Child-Pugh and equivalent to the MELD score in predicting outcome and even superior to MELD in predicting 30 day mortality (12). Calculating a MELD-Na or CLIF-SOFA score in the emergency department may help you in determining disposition for these patients and improve communication with your consultants.
What role if any does ammonia play in the evaluation of these patients?
Plasma ammonia is widely used in the evaluation of patients with cirrhosis and altered mental status, often as a surrogate of severity of hepatic encephalopathy (HE). Nicolao et al. from Munich evaluated the utility of blood ammonia levels alone for diagnosing HE in the emergency department. They found that higher plasma ammonia levels were correlated with more severe grades of HE, a relationship demonstrated as early as 1963 (13). However, they found that ammonia showed a 47.2% sensitivity and 78.3% specificity when compared to the West Haven criteria, the current gold standard for diagnosis of hepatic encephalopathy. The positive predictive value was 77.3% and the negative predictive value was 48.6% (7). In another study, more than half of the patients with West Haven Grade 0 (absence of HE) had an elevated ammonia level. Another study followed serial ammonia levels; in 17 patients who had resolution of their hepatic encephalopathy, several had no resolution in their hyperammonemia and 3 actually had an increase in ammonia levels (13). Ammonia levels should should not be used independently to diagnose or exclude hepatic encephalopathy. While there may be utility in trending ammonia, it should once again be used in conjunction with the patient’s clinical course, rather than in isolation.
Safety in Paracentesis
Patients with chronic liver disease are simultaneously prohemostatic and antihemostatic. One study of endoscopy assistant-performed 1,100 large volume paracentesis without ultrasound guidance showed no significant bleeding in any of 628 patients in which the platelet count and INR were neither considered nor corrected prior to the procedure. 84 of the patients had INR >/= 2.5 and 49 of the patients had platelet counts less than 20 (14). Another review found only 9 cases of severe bleeding out of 4729 reviewed large volume paracentesis (both ultrasound-guided and blind) over a ten year period, a 0.19% occurrence rate with a death rate of 0.016%. Bleeding was not related to operator experience, elevated INR, or low platelets. It occurred in patients with high MELD and Child-Pugh scores and all but one of the patients had some degree of renal dysfunction (15). In a study in India, low-risk procedures (abdominal paracentesis) and high-risk procedures (central vein cannulation) were performed on two groups of cirrhotic patients (Group A w/ INR >/= 1.5 and/or platelets >/= 50k; Group B INR < 1.5 and platelets > 50k) and found no significant difference in the rates of clinically significant bleeding (16).
Hepatorenal Syndrome (HRS)
The long and short of it is that pathophysiology of hepatorenal syndrome is not well understood. This is a functionally pre-renal kidney injury that results from dysfunction in the renal arterial system. There is a decrease in systemic vascular resistance secondary to primary arterial vasodilation in the splanchnic circulation triggered by portal hypertension. In advanced cirrhosis, arterial pressure is maintained through the renin-angiotensin system, the sympathetic nervous system, and in late stages, nonosmotic hypersecretion of ADH. These compensatory mechanisms help maintain effective arterial blood volume but have important effects on kidney function, particularly on sodium and solute-free water retention. This leads to ascites, edema, and kidney injury that can ultimately result in kidney failure. Bacterial translocation across the splanchnic vasculature, leading to an inflammatory response, is also hypothesized to play an important pathophysiological role in hepatorenal syndrome. It is often difficult to differentiate hepatorenal syndrome from acute kidney failure due to acute tubular necrosis from direct nephrotoxic substances (often aminoglycosides or diuretics) and/or pre-renal azotemia from sepsis or acute hypovolemia from a GI bleed (18).
Types of HRS
Type 1 HRS - rapidly progressive renal failure
Doubling of initial sCr to > 2.5 mg/dL in < 2 weeks
May appear spontaneously or w/ a precipitating event (i.e. SBP)
Very poor prognosis (more details)
Type 2 HRS - steady or slowly progressive course
Moderate renal failure (sCr > 1.5)
Usually spontaneous, usually in patients w/ refractory ascites
Survival worse than patients w/ ascites w/o renal failure
We will not be making the diagnosis of hepatorenal syndrome in the emergency department. However, we will be collecting data that will help the ICU physicians upstairs make the diagnosis after 48 hours (see criteria above). Serum creatinine is the best measure of renal function in these patients, although it may underestimate the degree of renal dysfunction owing to low baseline creatinine in these malnourished patients (19). Urine electrolytes and a FeNa < 1% may favor HRS over intrinsic cause of renal failure; however, the clinical picture is rarely that simple. These numbers are not interpretable if the patient is on diuretics; additionally, there are some early stages of pre-renal causes that have elevated FeNas. Renal ultrasound, however, has been useful in differentiating between intrinsic renal pathology and (18). These patients are often thrombocytopenic, as noted before, and might not mount robust leukocytic responses to infection, depending on the degree of hypersplenism. The prognosis of HRS is very poor, with 50% survival at 1 month and 20% at 6 months (18)
There are many challenges in managing these patients. Several studies have demonstrated the effectiveness of terlipressin, a vasopressin analogue, in conjunction with albumin in the management of HRS Type 1. However, this is not available in the United States. Midodrine and norepinephrine have been studied in conjunction with albumin and octreotide, respectively, but there is limited evidence of their efficaciousness. Until further evidence becomes available, take a thoughtful and individualized approach to these patients. Be thoughtful about using large volumes of crystalloid to resuscitate these patients. Consider the patient’s home diuretic regimen and degree of kidney dysfunction when initiating diuresis. Reach for norepinephrine and/or midodrine when choosing vasoconstrictive agents. Use the scoring systems above - MELD and CLIF-SOFA - to guide your disposition as patients with higher scores will need ICU management and may need early consideration for transplantation (20).
Post by Kelli Jarrell, MD
Peer Review and Editing by Ryan LaFollette, MD
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