Residency · Residency · Gastroenterology

Cirrhosis and Portal Hypertension

Definition and Classification

Cirrhosis

Cirrhosis represents the end-stage of chronic liver disease and is defined histologically by the combination of diffuse hepatic fibrosis, formation of regenerative nodules, and architectural distortion of the hepatic lobule. While traditionally considered an irreversible condition, it is now recognized that fibrosis regression and even reversal of cirrhosis can occur with successful treatment of the underlying etiology. This has been demonstrated following sustained virologic response in hepatitis C, viral suppression in hepatitis B, sustained alcohol abstinence, and adequate immunosuppressive therapy in autoimmune hepatitis.

Severity Classification

The Child-Turcotte-Pugh score incorporates five clinical and laboratory parameters: bilirubin, albumin, INR, severity of ascites, and grade of hepatic encephalopathy. Each parameter is scored from 1 to 3, yielding a total score from 5 to 15. Class A (score 5 to 6) represents compensated cirrhosis, Class B (7 to 9) indicates significant hepatic dysfunction, and Class C (10 to 15) corresponds to decompensated cirrhosis.

The Model for End-Stage Liver Disease score is a continuous scale derived from bilirubin, INR, and creatinine, with MELD-Na additionally incorporating serum sodium. The MELD 3.0 formula, adopted by UNOS in 2022, adds sex and albumin to improve equity in organ allocation. The MELD score is used for liver transplant allocation prioritization and provides accurate short-term mortality prediction.

The distinction between compensated and decompensated cirrhosis is of fundamental clinical importance. Decompensation is defined by the development of ascites, variceal hemorrhage, hepatic encephalopathy, or jaundice. The median survival drops precipitously from greater than 12 years in compensated cirrhosis to 2 to 4 years following the first episode of decompensation, underscoring the need for early transplant referral.

Portal Hypertension

Pathophysiology

Portal hypertension is quantified by the hepatic venous pressure gradient, which represents the difference between wedged hepatic venous pressure and free hepatic venous pressure. The normal HVPG is less than 5 mmHg. Clinically significant portal hypertension is defined by an HVPG of 10 mmHg or greater, which represents the threshold for the development of varices, ascites, and other complications. The variceal bleeding threshold occurs at an HVPG of 12 mmHg or greater.

The pathophysiology of portal hypertension involves two complementary mechanisms. First, increased intrahepatic resistance results from both structural factors (fibrosis, regenerative nodules compressing sinusoids) and dynamic factors (sinusoidal vasoconstriction mediated by reduced nitric oxide production and increased endothelin-1). Second, increased splanchnic blood flow develops as a consequence of splanchnic arteriolar vasodilation driven by excessive nitric oxide and prostaglandin production in the mesenteric circulation. This paradox of reduced nitric oxide in the intrahepatic circulation and excessive nitric oxide in the splanchnic circulation is central to the pathophysiology of portal hypertension.

The concept of compensated advanced chronic liver disease (cACLD) identifies patients with liver stiffness of 10 kPa or greater by transient elastography who may benefit from risk stratification for clinically significant portal hypertension without the need for invasive HVPG measurement.

Non-Invasive Identification of CSPH (Baveno VII, 2022)

The Baveno VII consensus introduced non-invasive criteria for identifying clinically significant portal hypertension. A liver stiffness measurement of 25 kPa or greater is sufficient to rule in CSPH, and these patients can be started on non-selective beta-blocker therapy without the need for esophagogastroduodenoscopy screening for varices. Conversely, a liver stiffness measurement below 15 kPa combined with a platelet count greater than 150,000 is sufficient to rule out CSPH, and variceal screening is not needed in these patients. When liver stiffness falls between 15 and 25 kPa, or when platelets are between 110,000 and 150,000, the results are indeterminate and EGD should be performed for variceal screening.

Variceal Hemorrhage

Primary Prophylaxis (Prevention of First Bleed)

Screening for esophageal varices with EGD should be performed at the time of cirrhosis diagnosis. If no varices are found, repeat endoscopy is performed every 2 to 3 years in compensated patients and annually in decompensated patients. Patients with no varices or small varices without high-risk features require no treatment and should undergo surveillance.

Small varices with high-risk features, defined as the presence of red wale marks or Child-Pugh C status, should be treated with a non-selective beta-blocker. For medium or large varices, the treatment options are a non-selective beta-blocker (first-line) or endoscopic variceal ligation.

Carvedilol is the preferred non-selective beta-blocker, administered at 6.25 mg twice daily (starting at 6.25 mg once daily and titrating). It provides both alpha-adrenergic and beta-adrenergic blockade, resulting in greater portal pressure reduction than propranolol. The PREDESCI trial demonstrated that carvedilol prevents first decompensation in patients with clinically significant portal hypertension, even in those without large varices, establishing a paradigm shift toward treating the underlying portal hypertension rather than waiting for variceal formation.

Propranolol at 20 to 40 mg twice daily titrated to a heart rate of 55 to 60 beats per minute and nadolol at 40 to 80 mg daily are traditional alternatives. Endoscopic variceal ligation involves band ligation performed every 2 to 4 weeks until variceal obliteration, with subsequent surveillance every 6 to 12 months. EVL achieves higher eradication rates but has higher variceal recurrence compared with non-selective beta-blockers.

The use of non-selective beta-blockers in patients with advanced decompensation remains controversial. Some evidence suggests potential harm in patients with refractory ascites or spontaneous bacterial peritonitis, and dose reduction or discontinuation should be considered when systolic blood pressure falls below 90 mmHg, when acute kidney injury develops, when spontaneous bacterial peritonitis occurs, or when hyponatremia below 120 mEq/L is present.

Acute Variceal Hemorrhage Management

The management of acute variceal hemorrhage requires a coordinated, multidisciplinary approach. Resuscitation should follow a restrictive transfusion strategy targeting a hemoglobin of 7 to 8 g/dL, as over-resuscitation increases portal pressure and worsens bleeding.

Pharmacotherapy with a somatostatin analogue should be initiated before endoscopy. Octreotide is given as a 50 microgram intravenous bolus followed by a 50 microgram per hour continuous infusion for 2 to 5 days. Where available, terlipressin is preferred based on the CONFIRM trial, which demonstrated a survival benefit. Prophylactic antibiotics with ceftriaxone 1 gram intravenously daily for 7 days are mandatory, as they reduce rebleeding, infectious complications, and mortality.

Urgent esophagogastroduodenoscopy should be performed within 12 hours. Endoscopic variceal ligation is the treatment of choice for esophageal varices, while tissue adhesive injection with cyanoacrylate is used for gastric varices (GOV2 and IGV1 types). Balloon tamponade with a Sengstaken-Blakemore or Minnesota tube serves as a temporizing measure for uncontrolled bleeding as a bridge to definitive therapy, with a maximum duration of 24 hours. Self-expanding metal stents (Danis or SX-Ella stents) placed in the esophagus represent a salvage option for refractory bleeding and can remain in place for 7 to 14 days.

Pre-emptive transjugular intrahepatic portosystemic shunt placement within 72 hours (ideally within 24 hours) is recommended for high-risk patients, defined as Child-Pugh C patients (score 10 to 13) or Child-Pugh B patients with active bleeding at the time of endoscopy. This approach, endorsed by Baveno VII, reduces rebleeding and improves mortality.

Secondary Prophylaxis (After First Variceal Bleed)

The combination of a non-selective beta-blocker plus endoscopic variceal ligation is the most effective strategy for secondary prophylaxis, reducing the rebleeding rate to 15 to 20% compared with 60% without prophylaxis. Transjugular intrahepatic portosystemic shunt placement is indicated for patients who experience recurrent variceal bleeding despite combined medical and endoscopic therapy, providing definitive portal decompression.

<image>A variceal management algorithm based on Baveno VII guidelines. Start with "Compensated advanced chronic liver disease (cACLD, LSM >= 10 kPa)." Decision path: "Assess for CSPH: LSM and platelets." Branch 1 "LSM >= 25 kPa (CSPH ruled IN)": "Start carvedilol 6.25 mg BID; EGD not mandatory for CSPH diagnosis." Branch 2 "LSM < 15 kPa + Platelets > 150K (CSPH ruled OUT)": "No variceal screening needed; repeat LSM annually." Branch 3 "Indeterminate (LSM 15-25 or Plt 110-150K)": "Perform EGD." After EGD, show variceal findings: "No varices" -> "Repeat EGD q2-3 years"; "Small varices without red signs" -> "NSBB or surveillance"; "Medium/Large varices" -> "NSBB (carvedilol preferred) or EVL." Separate box for "Acute variceal hemorrhage": "Octreotide + ceftriaxone + urgent EGD (<12h) + EVL. High-risk (CTP-B active bleeding or CTP-C): pre-emptive TIPS within 72h." Post-bleed: "NSBB + EVL combination for secondary prophylaxis." Use red for acute bleeding pathway, green for prevention, blue for surveillance. Include HVPG thresholds in a reference box: <5 normal, >=10 CSPH, >=12 variceal bleeding risk, >=20 treatment failure risk.</image>

Ascites

Pathophysiology

Ascites formation in cirrhosis results from the convergence of portal hypertension and splanchnic vasodilation. Portal hypertension combined with splanchnic arteriolar dilation leads to effective arterial underfilling, which activates the renin-angiotensin-aldosterone system, antidiuretic hormone secretion, and the sympathetic nervous system. These neurohormonal responses promote avid sodium and water retention, and the combination of elevated portal pressure and hypoalbuminemia drives the transudation of fluid into the peritoneal cavity. The threshold for ascites formation is generally an HVPG of 10 to 12 mmHg in combination with a serum albumin below 3 g/dL.

Diagnosis

Diagnostic paracentesis must be performed in all patients presenting with new-onset ascites, in all patients hospitalized with ascites (regardless of the reason for admission), and whenever clinical deterioration occurs. This recommendation cannot be overemphasized, as delay in performing diagnostic paracentesis increases mortality.

The serum-ascites albumin gradient is the key diagnostic test. A SAAG of 1.1 g/dL or greater indicates portal hypertension with 97% accuracy. The combination of a SAAG of 1.1 g/dL or greater with an ascitic fluid total protein below 2.5 g/dL is characteristic of cirrhotic ascites, while a SAAG of 1.1 g/dL or greater with a total protein of 2.5 g/dL or greater suggests cardiac ascites, Budd-Chiari syndrome, or myxedema. A SAAG below 1.1 g/dL indicates a non-portal hypertensive etiology such as peritoneal carcinomatosis, tuberculous peritonitis, nephrotic syndrome, or pancreatic ascites.

Management

Grade 1 (mild) ascites, detected only on imaging, requires only dietary sodium restriction. Grade 2 (moderate) ascites is managed with sodium restriction to 2 grams per day (88 mEq per day) combined with diuretic therapy. Spironolactone is the cornerstone diuretic, initiated at 100 mg per day and titrated to a maximum of 400 mg per day. As an aldosterone antagonist, it directly counteracts the neurohormonal mechanism driving sodium retention. Furosemide at 40 mg per day (maximum 160 mg per day) is added for synergistic effect and to maintain potassium balance. The spironolactone-to-furosemide ratio should be maintained at 100:40, and doses should be titrated every 3 to 5 days. The target weight loss is 0.5 kg per day in patients without peripheral edema and 1 kg per day in patients with edema. Fluid restriction is indicated only when serum sodium falls below 125 mEq/L.

Grade 3 (tense) ascites requires large-volume paracentesis with intravenous albumin replacement when more than 5 liters are removed, at a dose of 8 grams per liter of ascites removed. This albumin infusion prevents post-paracentesis circulatory dysfunction, a hemodynamic derangement that worsens renal function and increases mortality.

Refractory ascites, defined as ascites that does not respond to or cannot be managed with maximal diuretic therapy, is managed with serial large-volume paracentesis with albumin replacement every 2 to 4 weeks as needed. TIPS is the most effective treatment for refractory ascites, reducing ascites recurrence, though meta-analyses have not shown a consistent survival benefit (though individual studies suggest one). TIPS is relatively contraindicated in heart failure, severe hepatic encephalopathy, and MELD scores exceeding 18 to 20. The use of 8 to 10 mm covered stents is preferred. Long-term albumin infusion at 40 grams twice weekly showed survival benefit in the ANSWER trial for patients with refractory ascites, though this approach is not universally adopted. The ATTIRE trial, which studied albumin administration in hospitalized patients, was negative, though it evaluated a different population.

Spontaneous Bacterial Peritonitis (SBP)

Diagnosis

The diagnosis of spontaneous bacterial peritonitis requires an ascitic fluid polymorphonuclear cell count of 250 cells per cubic millimeter or greater, regardless of the culture result. Cultures are positive in only 40 to 50% of cases; inoculating blood culture bottles at the bedside with ascitic fluid improves the yield. The most common causative organisms are Escherichia coli, Klebsiella species, and Streptococcus pneumoniae, reflecting the monomicrobial, predominantly gram-negative nature of the infection.

Treatment

First-line antibiotic therapy is cefotaxime 2 grams intravenously every 8 hours for 5 days, or ceftriaxone 1 to 2 grams intravenously daily. Aminoglycosides must be avoided due to the unacceptable risk of nephrotoxicity in cirrhotic patients. Intravenous albumin is administered at 1.5 g/kg on day 1 and 1 g/kg on day 3, as demonstrated by the Sort trial to significantly reduce the incidence of renal failure and improve mortality.

Repeat paracentesis at 48 hours should demonstrate a decrease in polymorphonuclear cells of greater than 25%. If this response is not achieved, the antibiotic spectrum should be broadened and secondary peritonitis should be considered. Secondary peritonitis is suggested by polymicrobial cultures, very high PMN counts, failure to respond to appropriate antibiotic therapy, ascitic fluid protein exceeding 1 g/dL, glucose below 50 mg/dL, and LDH exceeding the serum level. Cross-sectional imaging and surgical consultation should be obtained.

SBP Prophylaxis

Lifelong prophylaxis is indicated after any episode of SBP, as the 1-year recurrence rate without prophylaxis is approximately 70%. Norfloxacin 400 mg daily, trimethoprim-sulfamethoxazole double-strength daily, or ciprofloxacin 500 mg daily reduces recurrence to approximately 20%. All cirrhotic patients with gastrointestinal hemorrhage should receive ceftriaxone 1 gram intravenously daily for 7 days. Primary prophylaxis with norfloxacin 400 mg daily is also indicated in patients with low ascitic fluid protein (below 1.5 g/dL) combined with liver failure (Child-Pugh score 9 or greater and bilirubin 3 or greater) or renal dysfunction (creatinine 1.2 or greater or sodium 130 or less), based on the Fernandez trial that demonstrated a survival benefit.

Hepatic Encephalopathy (HE)

Pathophysiology

Hepatic encephalopathy results primarily from the failure of the cirrhotic liver to adequately clear gut-derived ammonia from the portal circulation. Hyperammonemia leads to excessive glutamine synthesis in astrocytes, causing osmotic swelling of these cells (Alzheimer type II astrocytosis). Additional contributing mechanisms include increased GABAergic inhibitory tone, neuroinflammation, oxidative stress, and manganese deposition in the basal ganglia.

Precipitating factors must be systematically identified and addressed in every episode. The most common precipitants include infection (particularly spontaneous bacterial peritonitis), gastrointestinal bleeding, constipation, dehydration, electrolyte abnormalities (hypokalemia and hyponatremia), medications (benzodiazepines and opioids), TIPS placement, excessive protein intake (rare), and non-compliance with lactulose therapy.

Classification

Covert hepatic encephalopathy encompasses minimal and grade I encephalopathy. It is detected through psychometric testing using tools such as the number connection test, animal naming test, psychometric hepatic encephalopathy score, and the EncephalApp Stroop test. Covert encephalopathy is present in 30 to 50% of cirrhotic patients and significantly impairs driving ability, work performance, and quality of life. Overt hepatic encephalopathy (grades II through IV) is clinically apparent, with manifestations ranging from asterixis and disorientation to somnolence and coma.

Treatment

Identification and treatment of the precipitating factor is the single most important step in managing hepatic encephalopathy. Lactulose is the first-line pharmacologic agent, titrated to achieve 2 to 3 soft stools per day. Its mechanisms include osmotic laxation to reduce colonic ammonia absorption, reduction of ammonia-producing bacteria, and acidification of the colonic lumen, which traps ammonia as the non-absorbable ammonium ion. In the acute setting, lactulose 15 to 30 mL is administered orally every 1 to 2 hours until the first bowel movement, then transitioned to every 6 to 8 hours for maintenance.

Rifaximin is added to lactulose for secondary prophylaxis after the first episode of overt hepatic encephalopathy. At 550 mg twice daily, rifaximin reduced encephalopathy recurrence from 46% to 22% in the landmark Bass trial. It is a non-absorbed antibiotic that modulates the gut microbiome while minimizing systemic side effects, though it is expensive.

Nutritional support must include adequate protein at 1.2 to 1.5 g/kg/day. Protein restriction is harmful and outdated, promoting sarcopenia and paradoxically increasing ammonia generation from skeletal muscle catabolism. A late-evening snack prevents overnight catabolism and reduces morning ammonia levels. Branched-chain amino acid supplementation may benefit the rare patient who is genuinely protein-intolerant. L-ornithine L-aspartate enhances ammonia metabolism and has modest evidence supporting its use, particularly in the intravenous formulation. Zinc supplementation at 220 mg zinc sulfate twice daily addresses the common zinc deficiency in cirrhotic patients, as zinc is a cofactor for urea cycle enzymes.

Hepatorenal Syndrome (HRS)

Types (Revised ICA Criteria 2015)

HRS-AKI (formerly HRS type 1) is defined by an acute rise in serum creatinine of 0.3 mg/dL or greater within 48 hours or a 50% or greater increase within 7 days. It is rapidly progressive, usually precipitated by a triggering event such as spontaneous bacterial peritonitis, gastrointestinal bleeding, or large-volume paracentesis without albumin replacement, and carries a median survival of only 2 weeks without treatment.

HRS-NAKI (formerly HRS type 2) manifests as gradual renal function decline associated with refractory ascites and follows a steadily progressive course. Additional subcategories include HRS-AKD (acute kidney disease) and HRS-CKD (chronic kidney disease) for patients meeting hepatorenal syndrome criteria with these temporal patterns.

Diagnosis

The diagnosis of hepatorenal syndrome requires cirrhosis with ascites plus meeting AKI criteria. The diagnosis is one of exclusion: there should be no improvement after 48 hours of diuretic withdrawal and volume expansion with albumin at 1 g/kg/day for 2 days (maximum 100 grams per day). Patients should not have shock, should not be receiving nephrotoxic drugs, and should not have structural kidney disease as evidenced by an inactive urine sediment, proteinuria below 500 mg per day, and absence of obstructive uropathy.

Treatment

The combination of albumin and a vasoconstrictor is the mainstay of pharmacologic therapy. Terlipressin is preferred where available, based on the CONFIRM trial that demonstrated hepatorenal syndrome reversal in 32% of patients versus 17% with placebo. However, terlipressin carries a risk of respiratory adverse events requiring close monitoring. In settings where terlipressin is not available, the combination of octreotide and midodrine is used, though it is less effective. Norepinephrine infusion in the intensive care unit setting has demonstrated equivalent efficacy to terlipressin.

TIPS may improve renal function in carefully selected patients but is not appropriate for HRS-AKI with multi-organ failure. Renal replacement therapy serves only as a bridge to liver transplantation and is not beneficial as destination therapy. Liver transplantation is the definitive treatment, and combined liver-kidney transplantation should be considered when dialysis has exceeded 90 days or when underlying chronic kidney disease is present.

<image>A comprehensive cirrhosis complications overview diagram. Central image: cirrhotic liver (nodular, shrunken) with portal hypertension (dilated portal vein, collateral vessels). Radiating from the center, show five major complications with management summaries: (1) "Varices" (upper left): esophageal varices illustrated; management box: "NSBB (carvedilol) or EVL for prophylaxis; octreotide + EVL + ceftriaxone for acute bleed; pre-emptive TIPS if high-risk." (2) "Ascites" (lower left): distended abdomen with fluid wave; management box: "Na restriction + spironolactone/furosemide; LVP + albumin for tense; TIPS for refractory." (3) "SBP" (lower center): ascitic fluid bottle with PMN > 250; management box: "Cefotaxime + albumin day 1 and 3; norfloxacin prophylaxis." (4) "Hepatic Encephalopathy" (upper right): brain with asterixis hand illustration; management box: "Lactulose (2-3 stools/day) + rifaximin; identify precipitant; adequate protein." (5) "HRS" (lower right): kidney with reduced blood flow arrows; management box: "Albumin + terlipressin/midodrine+octreotide; liver transplant definitive." Include MELD score components in a corner box. Use organ-specific colors and include mortality/survival statistics for each complication.</image>

Key Clinical Pearls

• Baveno VII: liver stiffness of 25 kPa or greater rules in clinically significant portal hypertension, and carvedilol can be started without EGD. Liver stiffness below 15 kPa plus platelets above 150,000 rules out CSPH.
• Carvedilol is the preferred non-selective beta-blocker. The PREDESCI trial showed it prevents first decompensation in patients with clinically significant portal hypertension even without large varices.
• Pre-emptive TIPS within 72 hours for high-risk variceal bleeding (Child-Pugh C or Child-Pugh B with active bleeding) reduces rebleeding and mortality.
• Intravenous albumin with SBP on day 1 and day 3 reduces renal failure and mortality and must not be omitted.
• Protein restriction in hepatic encephalopathy is harmful. Patients should receive 1.2 to 1.5 g/kg/day of protein.
• Rifaximin added to lactulose for secondary hepatic encephalopathy prophylaxis reduces recurrence by 58% (Bass trial).
• Diagnostic paracentesis is mandatory for all hospitalizations with ascites. Delay in performing paracentesis increases mortality.
• Terlipressin improves HRS-AKI reversal but carries risk of respiratory adverse events and requires close monitoring.

References

1. de Franchis R, et al. Baveno VII — Renewing consensus in portal hypertension. J Hepatol. 2022;76(4):959-974.
2. Biggins SW, et al. Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: 2021 Practice Guidance by the AASLD. Hepatology. 2021;74(2):1014-1048.
3. Villanueva C, et al. Beta-blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI). Lancet. 2019;393(10167):1597-1608.
4. Bass NM, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071-1081.
5. Wong F, et al. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome (CONFIRM). N Engl J Med. 2021;384(9):818-828.

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