Management of ascites in cirrhosis and portal hypertension

A brief history of ascites and portal hypertension

Ascites is the pathologic accumulation of fluid in the peritoneal cavity. It is both the most frequent and prominent clinical sign of liver disease. Notwithstanding the near reflexive association of ascites with liver disease, the formation of ascites is caused by a variety of conditions that range from benign to sinister.

Descriptions of ascites exist in human history from as distant as 1600 years Before the Common Era. Hindu medical treatises, the Ebers Papyrus of Ancient Egypt, and Mesoamerican figurines with a protuberant abdomen and everted umbilicus testify to the experience of many cultures with ascites. Hippocrates, though lacking any knowledge of hepatic physiology, presciently observed “when the liver is full of fluid and this overflows into the peritoneal cavity, so that the belly becomes full of water, death follows.” Even the term ascites —derived from the Greek askos, a bag made of leather or sheepskin used to contain liquids—reflects its ancient origins.

Clinical findings

Common physical examination findings of ascites include diastasis of abdominal muscles, umbilical herniation, and bulging flanks. In the supine position, fluid pools in the flanks where percussion may be dull compared with more tympanic areas of the central abdomen. The examination findings are easily elicited with large-volume ascites. The findings are less obvious in those with smaller ascites volumes, obesity, and concomitant organomegaly.

Ultrasound is the best imaging modality for the detection of ascites; it is inexpensive, avoids ionizing radiation, is performed as point-of-care testing, and has the added benefit of capturing the liver architecture and portal vein patency (see Chapter 13 ).

Ascites is graded by its volume. Grade 1 ascites is mild and detectable only by radiographic imaging. Grades 2 and 3 reflect moderate and severe ascites, respectively. In the latter, there is obvious abdominal distention, which is frequently associated with the discomfort of a protuberant abdomen, particularly in previously asthenic individuals.

Portal hypertension and mechanisms of ascites formation

Ascites is the most common complication of portal hypertension arising from cirrhosis and the annual incidence is 5% to 10%. Ascites development is associated with a median survival of 2 years ^, and, absent an earlier development of other signs or symptoms, heralds the change from a compensated to a decompensated state.

Portal hypertension can arise from cirrhotic and noncirrhotic disease, though as a manifestation of portal hypertension, ascites is more common in disorders that increase hepatic sinusoidal pressure from either sinusoidal hypertension or postsinusoidal processes (heart failure, venous outflow obstruction such as Budd-Chiari syndrome; see Chapter 86 ). By comparison, ascites is less frequent in presinusoidal portal hypertension (e.g., extrahepatic portal vein thrombosis).

The splanchnic circulation consists of all the vasculature arising from the celiac, superior mesenteric, and inferior mesenteric arteries (see Chapters 2 and 5 ). Splanchnic arterioles are partially constricted under basal conditions and are responsive to a myriad of endothelial-derived substances, circulating vasoactive agents, and neurotransmitters.

The majority of the blood flow into the liver arises from the venous drainage of the splanchnic organs and conveyed into the liver by the portal circulation. Under normal conditions, portal blood (and hepatic arterial blood) enter the sinusoids at the portal tract and transverse the sinusoids to reach the hepatic vein. Sinusoids are separated from cords of hepatocytes by liver sinusoidal endothelial cells (LSECs), whose properties of being both fenestrated and lacking a basement membrane allow oxygen, cells, and plasma components to diffuse into the space of Disse wherein reside the hepatic stellate cells (HSCs) (see Chapter 7 ).

HSCs are the principal collagen-producing cells of the liver and elaborate extracellular matrix in response to liver injury rendering the fenestrations of the LSECs ineffective (see Chapter 7 ). These architectural changes in the hepatic microcirculation result in the static contribution to portal hypertension. Based on studies in animal models, these static changes account for 80% of the increase in resistance to portal flow. The remaining 20% of the resistance reflects dynamic forces influenced by HSCs that acquire a contractile, pericyte-like function. Molecular signaling to the HSCs through increased sensitivity to endothelin; ligand of the CXC chemokine receptor 4; dysfunctional nitric oxide–mediated signaling between LSECs and HSCs; and microvascular thrombosis have all been studied as mechanisms to explain LSEC response.

In the splanchnic circulation, different but equally important changes occur that contribute to portal hypertension. The most determinative change is splanchnic arterial vasodilation. In experimental models of cirrhosis, vasodilation is mediated by nitric oxide (NO)–dependent and NO-independent processes. An incomplete list of NO-independent processes includes vasodilatory natriuretic peptides, endocannabanoids, impaired sympathetic nervous system signaling, and overactivity of the enzyme heme oxygenase. Vasodilation in the splanchnic circulation decreases the effective arterial circulation, and increases in cardiac output compensate for the change.

To date, none of the signaling pathways that result in either dynamic HSC effects or splanchnic vasodilation has translated into therapies to counteract portal hypertension. In comparison, there are emerging therapies that may reduce or reverse hepatic fibrosis.

With the progression of portal hypertension, additional compensatory mechanisms marshal to maintain the arterial circulation in the face of even greater increases in splanchnic vasodilation. These mechanisms include activation of the renin-angiotensin-aldosterone system and sympathetic nervous system stimulation of renal sodium retention. Nonosmotic release of arginine vasopressin (antidiuretic hormone [ADH]) is an additional compensatory mechanism to increase the effective arterial volume, even at the expense of tonicity; this is often the mechanism for hyponatremia in decompensated cirrhosis.

The cumulative effects of increased hydrostatic pressure in the hepatic microcirculation, increased splanchnic volume, and hyperdynamic circulation (increased flow) lead to hepatic lymph formation in excess of its removal ( Fig. 79.1 ). The excess fluid weeps into the peritoneal cavity and is recognized as ascites.

Evaluation of ascites

Cirrhotic ascites is translucent but commonly takes on a yellow or amber color. The fluid typically has a low leukocyte (less than 100 μL/mm ³ ) and red blood cell content. The protein content is typically less than 2.5 mg/dL, and the protein content varies inversely with the severity of the portal hypertension. High protein content (ascites fluid protein greater than 2.5 mg/dL) is commonly seen in ascites arising from venous outflow obstruction from heart failure.

Measurement of the serum albumin ascites gradient (SAAG) is both a highly accurate and clinically facile technique for assessing the origins of ascites. The SAAG is calculated by subtracting the concentration of albumin in the ascites from that in the plasma. With an approximately 97% accuracy, a difference (called the gradient ) greater than 1.1 g/dL indicates the presence of portal or sinusoidal hypertension.

Opacification of the ascites fluid can arise from a number of disparate processes. Bloody ascites (hematocrit >0.5%) can be seen in traumatic paracentesis, spontaneous rupture of hepatocellular cancer, or hemorrhagic pancreatitis. Chylous ascites is milky in appearance from increased concentration of chylomicron-rich triglycerides (ascites triglyceride >100 mg/dL). ^, It arises from disruption of lymphatic flow, most commonly lymphagiectasia or lymphoma, but it can also occur with disseminated mycobacterial infections, cancers (Kaposi sarcoma, carcinoid tumors), abdominal trauma, or surgical disruption of the cisterna chyli. Cirrhotic ascites can also take on a chylous appearance owing to rupture of abdominal lymphatics from portal hypertension. In these cases, known as pseudochylous ascites, the triglyceride concentration is generally less than the threshold value of ascites triglyceride found in cases not arising from portal hypertension.

Both malignancy and tuberculosis peritonitis can result in ascites, and in both circumstances, the SAAG is less than 1.1 g/dL. Confusion may arise when liver disease coexists, as in the case of tuberculosis and alcohol-related liver disease. The diagnosis of malignant ascites is established by the finding of cancer cells within the peritoneal cavity. This can be diagnosed by cytology in combination with immunohistologic staining.

The peritoneum is a common site of involvement in tuberculosis, and in the United States the peritoneum is the sixth most common extrapulmonary site. Peritoneal cell counts typically vary between 500 and 1500 cells/mm ³ with a lymphocyte predominance in 68%, although the absence of a lymphocyte predominance does not exclude tuberculosis, particularly in patients with renal failure in whom the cells are mostly neutrophils. Mycobacterial culture of the fluid has a diagnostic sensitivity of 34% and requires several weeks of incubation. Measurement of adenosine deaminase activity in the peritoneal fluid has been proposed as another diagnostic test with high sensitivity and specificity, although the positive predictive value has been reported to be low in the setting of concomitant cirrhosis. Of all the diagnostic strategies, laparoscopy with peritoneal biopsy affords the highest sensitivity and specificity and permits exclusion of other granulomatous and nongranulomatous processes that can produce low-SAAG ascites. The ascites concentration of lactate dehydrogenase (LDH) tends to be higher than that of serum LDH in malignant ascites and less than half that of serum in tuberculous ascites.

Management of ascites

The primary goal of ascites management is to reduce ascites volume. This can be achieved by strategies that increase renal sodium excretion, mechanically remove the ascites, or reduce portal hypertension. It is only with reduction of portal hypertension that the fundamental physiologic mechanism responsible for ascites is addressed. Choosing the most appropriate therapy must consider the volume of ascites, the severity of the underlying liver disease, and the presence of renal dysfunction or electrolyte disorders.