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PBC—Susceptibility to Toxin Exposure

  1. Top of page
  2. PBC—Susceptibility to Toxin Exposure
  3. Portopulmonary Hypertension
  4. Adrenal Support for the Sick Patient With Cirrhosis
  5. Screening for Cholangiocarcinoma in PSC
  6. Blocking Hepatic Adenosine A1 Receptors Ameliorates the Hepatorenal Syndrome
  7. Urinary Aquaporin Excretion and Renal Water Retention in Cirrhosis

Over the years there have been various reports of environmental influences on the incidence of primary biliary cirrhosis (PBC). Initially, these centered on a temperate climate, then local reservoir supplies of drinking water, and more recently on the use of nail varnish and proximity to landfill sites for noxious waste. Support for the concept that susceptibility to PBC is conferred at least in part by inability to excrete chemicals of endogenous and exogenous origin in a biotransformed state is mounting irresistibly. Adherents to such an hypothesis would argue that immunological features constitute a secondary phenomenon and thus a consequence, rather than the cause of the disease. In their report, Zein et al. demonstrated a significant association of tobacco consumption with advanced hepatic fibrosis, defined as Ludwig stage 2 and stage 3 in PBC. Smokers (a lifetime consumption of more than 100 cigarettes) were at greater risk of advanced fibrosis (27/38, 71% versus 13/39, 33%. P < .0001). A smoking history of more than 10 pack years was similarly associated with greater risk of advanced fibrosis (27/38, 71% versus 7/37, 19%. P < .0001). The risk was confirmed in a second cohort of 175 patients with PBC. (See Fig.) Promotion of fibrosis may, like production of mitochondrial antibodies, be regarded as a reaction to disease, rather than the specific injury-generating disease itself in PBC; nevertheless, the results encourage the search for defective hepatic biotransformation mechanisms as the foundation of susceptibility to PBC. (See HEPATOLOGY 2006;44:1564–1571.)

Portopulmonary Hypertension

  1. Top of page
  2. PBC—Susceptibility to Toxin Exposure
  3. Portopulmonary Hypertension
  4. Adrenal Support for the Sick Patient With Cirrhosis
  5. Screening for Cholangiocarcinoma in PSC
  6. Blocking Hepatic Adenosine A1 Receptors Ameliorates the Hepatorenal Syndrome
  7. Urinary Aquaporin Excretion and Renal Water Retention in Cirrhosis

Pulmonary hypertension, when due to increased pulmonary vascular resistance (PVR) and the result of liver disease, is known as portopulmonary hypertension and may be reversed by liver transplantation. Patients with the most severely elevated mean pulmonary arterial pressure (MPAP) tend to fare poorly with liver transplantation and run a high risk of intraoperative death from right heart failure. Krowka et al. report on a 10-year experience of assessing 1235 liver transplant candidates according to a protocol in which echocardiography was used to screen for portopulmonary hypertension. In 101 patients, a right ventricular systolic pressure (RVSP) was estimated as >50 mm Hg prompted further work-up by right heart catheterization. The key element of portopulmonary hypertension is increased PVR, which cannot be readily reversed. In some patients, high pressure occurs even though PVR is normal or low when it is the consequence of the high cardiac output seen cirrhosis, or even an elevated left atrial filling pressure (measured as pulmonary artery occlusion pressure). Using guideline criteria of MPAP > 25 mm Hg and PVR > 240 dynes s · cm−5, portopulmonary hypertension was documented in 66 of the 101 patients. Adherence to this protocol is commended by the fact that all patients with MPAP > 35 mm Hg were identified by echocardiography so that no patient had a transplant operation canceled at the last minute due to an unexpected finding of severe pulmonary hypertension. (See HEPATOLOGY 2006;44:1502–1510.)

Adrenal Support for the Sick Patient With Cirrhosis

  1. Top of page
  2. PBC—Susceptibility to Toxin Exposure
  3. Portopulmonary Hypertension
  4. Adrenal Support for the Sick Patient With Cirrhosis
  5. Screening for Cholangiocarcinoma in PSC
  6. Blocking Hepatic Adenosine A1 Receptors Ameliorates the Hepatorenal Syndrome
  7. Urinary Aquaporin Excretion and Renal Water Retention in Cirrhosis

Recent reports have shown suboptimal responsiveness of the adrenal cortex to stress from sepsis in patients with cirrhosis in an intensive care setting. Administration of exogenous hydrocortisone has been shown to have numerous advantages, including restoration of responsiveness to the pressor actions of the renin-angiotensin system and infused norepinephrine; however, no survival benefit had been shown. Fernandez et al. performed the short corticotropin test on 25 successive patients admitted to the intensive care unit with cirrhosis and septic shock. A baseline plasma cortisol concentration <15 μg/dL or a rise of <9 μg/dL in patients with a baseline cortisol concentration <35 μg/dL following synacthen stimulation, was deemed diagnostic of relative adrenal insufficiency. These features were detected in 17 patients (68%) who were consequently treated with intravenous hydrocortisone (50 mg/6 hours). The outcome in this group was compared to that of the previous consecutive series of 50 patients admitted with cirrhosis and septic shock in whom no corticotropin stimulation test had been performed and no hydrocortisone administered. The hydrocortisone-treated group had better rates of resolution of shock, intensive care unit survival, and hospital survival (64% versus 32%, P = .003) when compared with the retrospective cohort. (See Fig.) (See HEPATOLOGY 2006;44:1288–1295.)

Screening for Cholangiocarcinoma in PSC

  1. Top of page
  2. PBC—Susceptibility to Toxin Exposure
  3. Portopulmonary Hypertension
  4. Adrenal Support for the Sick Patient With Cirrhosis
  5. Screening for Cholangiocarcinoma in PSC
  6. Blocking Hepatic Adenosine A1 Receptors Ameliorates the Hepatorenal Syndrome
  7. Urinary Aquaporin Excretion and Renal Water Retention in Cirrhosis

Lack of a reliable screening tool for detection of cholangiocarcinoma (CC) in primary sclerosing cholangitis (PSC) is of great concern. Imaging with CT, MRI, and ultrasound and measurement of various tumor markers in blood have been of no avail. The impact is massive, as by the time CC is diagnosable by any of these methods, the tumor has already progressed to the point where liver transplantation cannot be justified given the high recurrence and poor survival rates. The lifetime risk of CC in PSC is of the order of 15%-30% but prophylactic transplant cannot be justified merely to avert this risk. Positron emission tomography (PET) is the latest technique to promise some advance in detection of early tumors. Prytz et al. report on the results of screening with dynamic PET using 2-[18F]fluoro-2-deoxy-D-glucose (FDG) in 24 consecutive patients with PSC within 2 weeks of being listed for transplantation. PET correctly identified all 3 patients with CC as well as giving a false positive result in one patient with epithelioid cell granulomas in the explanted liver. A single patient with high-grade dysplasia had a negative result. One patient did not undergo transplantation because of a diagnosis of disseminated CC made while on the transplant waiting list. One patient died of CC 7 months after transplant and another died due to stricturing the duodenum by CC, although none had been detected within the explanted liver. The series therefore offers evidence of increased sensitivity for the diagnosis of CC in patients with PSC during evaluation for liver transplantation but, allowing for small numbers, does not encourage optimism that early detection of CC by PET would greatly improve the prospects of its cure. (See HEPATOLOGY 2006;44:1572–1580.)

Blocking Hepatic Adenosine A1 Receptors Ameliorates the Hepatorenal Syndrome

  1. Top of page
  2. PBC—Susceptibility to Toxin Exposure
  3. Portopulmonary Hypertension
  4. Adrenal Support for the Sick Patient With Cirrhosis
  5. Screening for Cholangiocarcinoma in PSC
  6. Blocking Hepatic Adenosine A1 Receptors Ameliorates the Hepatorenal Syndrome
  7. Urinary Aquaporin Excretion and Renal Water Retention in Cirrhosis

In a previous HEPATOLOGY report highlighted in the Hepatology Highlights, it was shown that the hepatorenal reflex could be attenuated by blockade of afferent adenosine signaling from the space of Mall, a small fluid space surrounding the terminal branches of the hepatic arterioles, portal venules, and hepatic nerves. It is thought that adenosine is secreted at a constant rate into this space and that its washout by blood flow is the key step in feedback regulation of the reciprocity of portal venous and hepatic arterial blood flow as well as stimulation of hepatorenal reflexes that influence fluid retention by the kidneys. Hepatic thirst for increased perfusion produces a signal for salt and water conservation, resulting in renal afferent vasoconstriction and ultimately the potential for developing hepatorenal syndrome. In models of cirrhosis, reflex renal vasoconstriction and oliguria could be prevented by intraportal infusion of the nonselective adenosine receptor antagonist 8-phenyl theophylline. Ming et al. extended these observations to the rat model of thioacetamide-induced acute liver failure. They showed that renal salt and water retention could be blocked by intraportal infusion of 8-cyclopentyl-1,3-dipropylxanthine an adenosine A1 receptor antagonist, but not by specific blockade of the A2 receptor. Adenosine A1 receptor blockade was effective when the antagonist was administered into the portal circulation but not after infusion into the systemic circulation. The work is a stimulus to search for specific afferent adenosine receptors that would gain ready access to the space of Mall and mitigate against liver-induced impairment of renal function—prognostically one of the gravest complications of both chronic and acute liver failure. (See HEPATOLOGY 2006;44:813–822.)

Urinary Aquaporin Excretion and Renal Water Retention in Cirrhosis

  1. Top of page
  2. PBC—Susceptibility to Toxin Exposure
  3. Portopulmonary Hypertension
  4. Adrenal Support for the Sick Patient With Cirrhosis
  5. Screening for Cholangiocarcinoma in PSC
  6. Blocking Hepatic Adenosine A1 Receptors Ameliorates the Hepatorenal Syndrome
  7. Urinary Aquaporin Excretion and Renal Water Retention in Cirrhosis

Studies on the renal mechanisms of excessive water retention, which causes dilutional hyponatremia, in association with advanced liver disease are entering a new phase. Water reabsorption from renal tubules requires not only a favorable solute concentration gradient but also pores for the water molecules to exit renal tubules via a family of proteins named aquaporins. Excretion of aquaporin 2 in urine has been shown to correlate with vasopressin-stimulated water retention in experimental animal and human models of overhydration and water deprivation. Vasopressin has an immediate effect on aquaporin 2 concentrations within the apical membrane of collecting duct principal cells by stimulating its incorporation from a reservoir of cytoplasmic vesicles and a longer term effect by stimulating gene transcription. Given that 3%-4% of renal aquaporin is shed into the urine on a daily basis, increased vasopressin activity is reflected by an increase in urinary aquaporin 2 excretion in experimental animals and in human congestive cardiac failure. Inaccessibility of renal tissue for direct studies in patients with cirrhosis has resulted in conflicting reports based on indirect evidence. Esteva-Font et al. report a significant fall in urinary aquaporin 2 excretion in patients with cirrhosis and ascites, which is still more marked in the presence of hyponatremia and hepatorenal syndrome. (See Fig.) Furthermore, they found no correlation of aquaporin 2 excretion with vasopressin activity. The patients studied by Esteva-Font et al. were chosen because of their stable state; e.g., hyponatremia, when studied, had existed for an average of 49 days. These single time point observations would therefore appear to reflect a steady state in which an escape mechanism dissociated aquaporin 2 expression from its augmentation by vasopressin. The authors argue that should such tachyphylaxis not operate, progressive hyponatremia would have been an inevitable and fatal consequence. Dynamic studies are therefore required in patients with cirrhosis of the acute changes that result in water retention and hyponatremia, during which it is likely that aquaporin 2 responsiveness to vasopressin will be preserved and pathogenetically implicated. (See HEPATOLOGY 2006;44:1555–1563.)