Cardio-hepatic syndrome: The overlooked crosstalk between heart and liver

Heart failure (HF) is a major public health concern with an increasing prevalence, a trend driven by population aging, improved therapeutic management, and extended life expectancy in affected patients(¹⁾. Recent studies have highlighted a shift in the prevalence of HF phenotypes, specifically an increase in the incidence of HF with preserved ejection fraction (HFpEF) and a decline in the incidence of HF with reduced ejection fraction (HFrEF). This shift is attributed to a combination of social and dietary factors, as well as advances in the treatment of conditions involved in HF pathophysiology, such as hypertension, diabetes mellitus, and dyslipidemia(¹⁾.
HF is a clinical syndrome that affects multiple systems and organs, including the brain, lungs, kidneys, skeletal muscles, adipose tissue, intestines, liver, and immune system(²⁾. The liver’s complex vascularization and high metabolic activity make it particularly susceptible to circulatory disturbances. The prevalence of hepatic injury in HF ranges between 15% and 65%(²⁾.
The main mechanisms involved in the development of hepatic injury in patients with HF include:

• Passive hepatic congestion: the absence of valves in the hepatic veins allows the transmission of increased pressure from the inferior vena cava to the hepatic sinusoids, leading to centrilobular congestion, sinusoidal dilation, and perivenular fibrosis. The lesions predominantly affect zone 3 of the hepatic lobule, while the periportal region remains intact(³⁾.
• Ischemia-reperfusion injury: hepatic damage results from hypoxia induced by hypoperfusion, which paradoxically worsens upon the restoration of cellular oxygenation. The characteristic histological lesion in this setting is centrilobular coagulative necrosis in zone 3, which may extend to adjacent hepatocytes(³⁾.

The main types of hepatic dysfunctions in patients with HF are acute cardiogenic liver injury (ACLI) and congestive hepatopathy(³⁾. ACLI, also referred to as hypoxic or ischemic hepatitis, has traditionally been considered a consequence of cardiogenic shock. However, recent studies have shown that patients with chronic congestion or hypertension can develop ACLI even in the presence of minor circulatory disturbances(³⁾. Thus, both hepatic hypoperfusion and congestion can lead to ischemic hepatitis(³⁾. The diagnosis of ACLI requires the fulfillment of three criteria:

• Clinical context: presence of heart failure and circulatory insufficiency.
• Laboratory findings: a significant increase (10- to 20-fold above normal) in aminotransferase and lactate dehydrogenase (LDH) levels within 1–3 days following hemodynamic deterioration.
• Exclusion of other causes of liver injury(³⁾.

Clinically, these patients often remain asymptomatic or may develop manifestations similar to those of acute viral hepatitis(³⁾. A serum alanine aminotransferase (ALT)/lactate dehydrogenase (LDH) ratio of <1.5 is suggestive of ACLI³. Additionally, patients may present with hemorrhagic diathesis due to hepatic coagulation factor deficiency and elevated serum bilirubin levels, secondary to hepatocellular injury or cholestasis(³⁾. They also frequently exhibit azotemic retention syndrome(³⁾.

Abdominal ultrasound can support the diagnosis by revealing inferior vena cava and hepatic vein dilation, indicative of passive congestion(³⁾. The role of computed tomography (CT) and magnetic resonance imaging (MRI) is primarily to exclude other causes of liver injury(³⁾. Liver biopsy is recommended only when the diagnosis remains uncertain(³⁾.

The therapeutic management of these patients involves treating the underlying acute HF, administering positive inotropic agents in cases of persistent hypoperfusion, providing oxygen therapy for hypoxemia, and considering mechanical circulatory support devices or heart transplantation in advanced stages of HF(³⁾. After hemodynamic stabilization, aminotransferases and LDH levels typically return to normal within 7–10 days. However, despite appropriate management, mortality remains high(³⁾.

Congestive hepatopathy has a reported incidence of 15–65% in patients with HF³. The main pathophysiological mechanisms underlying this condition include elevated hepatic venous pressure and reduced hepatic blood flow, leading to decreased arterial oxygen saturation³. These patients are often asymptomatic, with the diagnosis suggested only by abnormal liver function tests detected during routine evaluation. However, some may present with hepatomegaly, right upper quadrant discomfort due to hepatic capsule distension, sclero-cutaneous jaundice, and ascites³. In end-stage biventricular HF, distinguishing between chronic congestive hepatopathy and liver cirrhosis becomes challenging. A suggestive sign of tricuspid regurgitation is the presence of systolic pulsations in the right upper quadrant or epigastrium (Harzer’s sign). The disappearance of these pulsations indicates progression to cardiac cirrhosis(³⁾.

The diagnosis of congestive hepatopathy is based on the correlation of clinical findings with laboratory data. The key biochemical alterations identified in these patients include:

• Hyperbilirubinemia, predominantly unconjugated bilirubin, present in 70% of patients. Total bilirubin levels typically do not exceed 3 mg/dL and correlate with right atrial pressure, serving as a prognostic marker.
• Mildly elevated alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) levels, which also act as prognostic markers.
• Mildly elevated serum aminotransferases, observed in approximately one-third of patients.
• Hypoalbuminemia, found in 30–50% of patients (rarely below 2.5 g/dL), secondary to malnutrition and protein-losing enteropathy due to increased intestinal lymphatic pressure.
• Prolonged prothrombin time, resulting from reduced hepatic synthesis of coagulation factors II, VII, IX, and X.
• Elevated NT-proBNP levels, which may aid in differentiating cardiac cirrhosis from cirrhosis of other etiologies(³⁾.

Abdominal ultrasound with Doppler vascular examination plays a crucial role in the evaluation of these patients. It can reveal the following findings: hepatomegaly, dilation of the inferior vena cava (>21 mm) and hepatic veins (>7 mm), loss of the normal triphasic flow in the hepatic veins, reversed or diminished hepatic venous flow (in severe right heart failure, retrograde venous flow may be observed), reduced portal venous flow velocity (<15 cm/sec) and ascites³. Persistent hepatic congestion leads to hepatic fibrosis and, eventually, cardiac cirrhosis. Impulse elastography (FibroScan) and advanced ultrasound techniques using Shear Wave Elastography (SWE) allow for the assessment of hepatic fibrosis severity(⁴⁾.

The cornerstone of treatment for these patients is diuretic therapy. Additionally, the following interventions may be required:

• Positive inotropic support in cases of persistent hypotension.
• Interventional or surgical treatment for conditions such as constrictive pericarditis, tricuspid regurgitation/stenosis, or ischemic cardiomyopathy.
• In severe cases, the use of a left ventricular assist device (LVAD) or heart transplantation may be necessary(³⁾.

The prognosis of patients with congestive hepatopathy depends on the underlying cardiac condition. Elevated hepatic biomarkers are associated with hemodynamic abnormalities and reduced survival. Additionally, hypoalbuminemia and increased liver stiffness have been identified as markers of poor prognosis(³⁾. The MELD-Na (Model for End-Stage Liver Disease with Sodium) score is a reliable predictor of mortality and can also indicate the need for heart transplantation or left ventricular assist device (LVAD) implantation within one year³. Heart transplantation can significantly improve liver function, but cardiac cirrhosis is an absolute contraindication for heart transplantation—except in cases where a combined heart-liver transplant is performed(³⁾.

Hepatic dysfunction can alter the pharmacokinetics and pharmacodynamics of medications used in the treatment of heart failure (HF). However, guidelines on dose adjustments or modifications in administration frequency for patients with liver impairment remain unclear.

In conclusion, the relationship between cardiac dysfunction and hepatic dysfunction is bidirectional. Cholestatic syndrome is associated with signs of congestion, while hepatic cytolysis syndrome is linked to hepatic hypoperfusion. The histological changes induced by hepatic congestion can be reversible if therapeutic intervention occurs at an early stage. However, persistent congestion over months or years may lead to the development of cardiac cirrhosis(⁴⁾.

REFERENCES
1. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics-2023 update: A report from the American Heart Association. Circulation 2023;147(8):e93-e621.
2. Ciccarelli M, Dawson D, Falcao-Pires I, et al. Reciprocal organ interactions during heart failure: a position paper from the ESC Working Group on Myocardial Function. Cardiovasc Res. 2021;117(12):2416-2433.
3. Xanthopoulos A, Starling RC, Kitai T, Triposkiadis F. Heart failure and liver disease: cardiohepatic interactions. JACC Heart Fail. 2019;7(2):87-97.
4. Suffredini G, Gao WD, Dodd-O JM. Ultrasound shear wave elastography evaluation of the liver and implications for perioperative medicine. J Clin Med. 2024;13(13):3633.