A Resident's Guide to the CCU
Multisystem Involvement

Hepatorenal Syndrome (HRS) vs. Acute Decompensated Heart Failure

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Case Presentation:

54-year-old male with CAD s/p PCI to the LAD 2 years prior, HFpEF, and alcoholic cirrhosis complicated by ascites requiring large-volume paracentesis, spontaneous bacterial peritonitis, esophageal varices s/p clipping, and hepatic encephalopathy who is being evaluated in the emergency department by the CCU team for 1 week of increased swelling in his abdomen and lower extremities, dyspnea on exertion, and decreased urine output. He reports associated fatigue and some mild confusion. He denies any fevers, chills, abdominal pain, or chest pain. He reports no recent changes to his medications. 

Vitals: Afebrile, HR 100s, BP 90-100s/60-70s, and saturating >95% on room air 

Labs: HS-Troponin peak at 120, BNP 900 (previous 450), lactate 2.5. Cr notably elevated at 2.5 (baseline 1.3). LFTs with total bilirubin of 5.2 mg/dL (indirect bilirubinemia), AST of 83 U/L, ALT of 59 U/L, and albumin of 2.6 g/dL. Urinalysis unremarkable 

CXR: Cardiomegaly with slight pulmonary vascular congestion  

EKG: Normal sinus rhythm with rates in the 100s. Normal axis / intervals. No ST elevations / depressions. Non-specific T wave inversions in V5 and V6.

Interventions: Diagnostic paracentesis revealed a serum albumin-ascites gradient of 1.3 g/dL and PMN count of 178 cells/mm3. 

Cardiac history: most recent transthoracic echocardiogram 6 months ago with LVEF of 55-60% with notable diastolic dysfunction 

  

Home medications:
- Furosemide 40 mg twice daily 

- Spironolactone 25 mg once daily 

- Empagliflozin 10 mg daily 

- Enalapril 10 mg once daily 

- Metoprolol 50 mg once daily 

- Aspirin 81 mg once daily 

- Lactulose 30 mL twice daily with goal of ~3-5 bowel movements daily 

Social history: heavy alcohol use with 10-12 standard drinks per day for the past 30 years and is currently unemployed and lives alone 

Physical examination: appears tired and mildly confused, icteric sclerae noted and spider nevi present on skin exam, abdominal exam with no tenderness to palpation but shifting dullness with distension is present, 2+ pitting edema in lower extremities bilaterally 

Abdominal ultrasound findings:  Cirrhotic liver morphology with moderate ascites.  Patent portal and hepatic veins No focal lesions identified on the liver, no biliary obstruction noted

Ask Yourself:

Questions:

1. What should the initial approach be to this patient? 

2. What is the pathophysiology of hepatorenal syndrome and how is it different from cardiorenal syndrome? 

 

3. Why is hepatorenal syndrome important to understand and identify?

Background:

When a patient presents with a chief complaint of swelling in the abdomen or legs, it is important to determine the etiology for the hypervolemic state as this will help guide the patient’s treatment. Many times, a patient’s overload can be due to dysfunction from the heart, kidneys, and liver. Unlike fluid overload states that result from heart and kidney failure, hypervolemia secondary to liver failure is not treated primarily with diuresis. 

While liver injury has many etiologies, the most common in the Western world are alcoholic liver disease, fatty liver disease, and hepatitis C. Cirrhosis is caused by chronic liver injury, and it is hard to estimate how many people actually have cirrhosis due to the fact that many people may be compensated and asymptomatic. On histology, cirrhosis will present as regenerative nodules surrounded by fibrosis.

Patients with advanced cirrhosis frequently experience complications from the disease process, such as hepatic encephalopathy, varices (can be esophageal, gastric, or rectal), spontaneous bacterial peritonitis, hepatocellular carcinoma, and ascites. Unfortunately, the only cure for cirrhosis is liver transplantation.

Hepatorenal Syndrome (HRS)

As liver disease progresses, many organs become affected due to the maladaptive pathophysiology of cirrhosis. A major complication includes hepatorenal syndrome (HRS), which can be divided into two main categories–HRS-AKI  (i.e. acute renal dysfunction) vs HRS-CKD (i.e. chronic renal dysfunction due to the progression of liver disease). Reported mean survival of HRS-AKI/HRS-1 without liver transplantation is 2-3 weeks if untreated and 6-8 months for untreated HRS without AKI/HRS-2. 

  • HRS-AKI is defined as rapidly progressive kidney failure with initial serum creatinine doubling to levels of > 2.5 mg/dL or by 50% reduction in creatinine clearance to level < 20 mL/min in < 2 weeks. 

  • HRS-CKD is defined as more of a steady renal failure with serum creatinine > 1.5 mg/dL. 

HRS is driven by the underlying principle of intense renal vasoconstriction and activation of the renin-angiotensin-aldosterone system due to low effective circulating volume from blood pooling in the splanchnic circulation, loss of intravascular volume due to ascites, and subsequent peripheral arterial vasodilation. Additionally, the low oncotic pressure from hypoalbuminemia also results in third spacing. That said, the treatment for HRS is to give albumin to help increase the effective circulating volume and reduce the third spacing. If the patient is hypotensive and requires ICU level care, the first line pressor would be norepinephrine, which will help peripheral perfusion. Otherwise, Terlipressin and midodrine with octreotide can be used to reduce the splanchnic pooling of blood and increase renal perfusion.  

If not treated appropriately, hepatorenal syndrome can end in death. As such, prompt diagnosis and treatment is crucial. While the patient will ultimately need a liver transplant, the disease process can be tempered with medications, as mentioned above.

How to differentiate HRS from ADHF?

Get a right upper quadrant ultrasound (RUQUS) to see whether or not the patient has cirrhosis. If this shows cirrhosis, it is very likely that the liver may be to blame for the hypervolemia. However, it is important to note that cardiac pathologies can cause cirrhosis (aka Cardiac Cirrhosis) due to the increased central venous pressure causing congestive hepatopathy. Therefore, getting a TTE to rule out cardiac involvement is crucial. Remember— cirrhosis usually decreases the systemic vascular resistance, thereby increasing cardiac output. As such, you will expect patients with cirrhosis to have a higher than normal ejection fraction (i.e. >55%). If the ejection fraction is low, this might mean the heart was the primary issue or that the patient has severely progressed cirrhosis and heart failure. 

Other tests that help you rule out cardiac involvement include BNP, EKGs, and CXR (which you expect to not have any pulmonary vascular congestion or cardiomegaly).  

When patients have heart failure with venous congestion, this can cause increased venous volume with higher hydrostatic pressure that leads to ascites. Cardiac ascites can be distinguished between cirrhosis ascites by tapping the abdominal fluid. In both situations, the serum-ascites albumin gradient (SAAG) will be >1.1. However, the total protein will be <2.5 in cirrhosis ascites and >2.5 in cardiac ascites.

Renal Injury

Causes of AKI in patients with cirrhosis: 

  •  Large intravascular volume depletion (i.e. GI bleed, increased diuresis, diarrhea, etc)

  • Acute tubular necrosis (ATN) due to sepsis

  • Nephrotoxins (NSAIDs, aminoglycosides)

  • Glomerular disease

  • Tense ascites causing abdominal compartment syndrome (ultimately decreasing renal blood flow)

  • Hepatorenal Syndrome (diagnosis of exclusion!!) 

Remember! HRS is a type of pre-renal AKI due to problems with hemodynamics, NOT volume depletion. Therefore, if the AKI gets better with albumin and stopping diuretics, the cause of the AKI is likely due to volume depletion. If albumin does NOT help the creatinine, HRS is high on the differential.

In HRS, you will see:

  • Increased serum Cr (>.3) 

  • Normal urine sediment

  • Minimal proteinuria 

  • Decreased urine sodium

  • Oliguria (<500 mL urine / day)

Medications and Interventions:

Medications / Interventions: 

  • Stop any nephrotoxins (such as NSAIDs) which may worsen renal injury

  • Stop all diuretics as to not cause any further volume depletion and decreased renal perfusion

  • Volume expansion

    • Albumin (1 gram / kg divided into two doses over the first two days, followed by 20-40 grams / day. Using 5% vs 25% depends on the patient’s overall volume status) 

  • Vasoconstrictors

    • Midodrine: An oral alpha 1 agonist 

    • Octreotide: A somatostatin analogue that specifically works to help splanchnic vasoconstriction

    • Norepinephrine (1st drug of choice when hypotensive!), vasopressin, terlipressin (which theoretically is more specific to splanchnic vessels) 

  • Antibiotics 

    • If you are concerned about any type of bleed, add antibiotics as this has been shown to help decrease length of stay and mortality. As infection is a very common reason patients with cirrhosis decompensate, adding empiric antibiotics can help treat the potential underlying pathology.  

  • Transjugular Intrahepatic Portosystemic Shunt (TIPS)

    • Helps to relieve the pressure from the portal system by connecting the hepatic vein and the intrahepatic branch of the portal vein.

Back to the Case:

1. What should the initial approach be to this patient? 

This patient is being admitted for volume overload. It is unclear at this time whether the primary process driving this volume overload is due to the heart or the liver. While there is usually one organ driving the hypervolemia, it is important to recognize that the hypervolemia may be multifactorial. Important labs to get are BNP, troponin, lactate, BMP for creatinine, CBC, LFTs, and UA. Don’t forget to order an infectious workup as sepsis can worsen hepatorenal pathology by causing systemic vasodilation!! Additionally, you should also get an EKG, TTE (if the patient has not had one in >1 year), and RUQUS can help further point you towards the heart vs the liver. Most importantly, the patient will need a paracentesis to help establish whether this is primary liver vs cardiac pathology. Remember that the SAAG will be >1.1 in both cardiac vs hepatic ascites; however, the total protein will be <2.5 in cirrhosis ascites and >2.5 in cardiac ascites. 

2. What is the pathophysiology of hepatorenal syndrome and how is it different from cardiorenal syndrome? 

What makes this case interesting is that it highlights the similarities between decompensated heart failure and decompensated cirrhosis. Despite this, there remains subtle, yet crucial, differences which allow us to appropriately manage each of these conditions. 

  • Hepatorenal syndrome occurs in patients with advanced hepatic cirrhosis or fulminant hepatic failure. There is reversible renal impairment characterized by an increase in Cr and reduction in both GFR and renal plasma flow without any other identifiable causes of renal failure. HRS consists of intense renal vasoconstriction with preservation of tubular function. Thus, no histological changes are noted and there is no proteinuria usually. Peripheral arteries are undergoing profound vasodilation in hepatorenal syndrome due to increased splanchnic blood pooling from increased resistance of blood flow through the diseased liver resulting in a reduction of effective circulating volume. Consequently, this leads to activation of the renin-angiotensin-aldosterone system which in turn causes hyperdynamic circulation with increased cardiac output, decreased systemic vascular resistance, vasoconstriction of renal vasculature, and hypotension. In hepatorenal syndrome, there is also an increase in vasodilator production. 

  • Cardiorenal syndrome can be caused by dysfunction of either the heart or kidneys that in turn causes dysfunction in the other organ. While poor renal perfusion due to a decompensated heart as a result of poor forward flow was thought to cause this phenomena, increased central venous congestion (which decreases the difference between arterial driving pressures and venous outflow pressure) can cause renal venous hypertension and increase renal resistance, which can ultimately impair intrarenal blood flow. 

3. Why is hepatorenal syndrome important to understand and identify? 

The most important reasons why HRS is important to understand and identify are treatment and prognosis. In terms of treatment, it is well understood that cardiorenal syndrome and acute decompensated heart failure are treated with aggressive diuresis and close monitoring of renal function. Other therapies that are crucial include ACE inhibitors and angiotensin receptor blockers. In contrast, initial pharmacologic therapy for HRS-AKI in the US is midodrine and octreotide or albumin with norepinephrine. Terlipressin plus albumin is a combination that is used in Europe and the CONFIRM trial has shown it to reduce length of ICU stay in patients with HRS. It has been approved by the FDA as of 2022 for the treatment of adults hospitalized with HRS-AKI. We anticipate it being available shortly for use for our patients with HRS-AKI. Lastly, HRS-AKI carries a grim prognosis. Reported mean survival of HRS-AKI/HRS-1 without liver transplantation is 2-3 weeks if untreated and 6-8 months for untreated HRS without AKI/HRS. It is important to note that heart failure in patients with cirrhosis or HRS is a clinical diagnosis.  

Further Learning:

Attending / Fellow pearls: 

  • Remember that HRS is a diagnosis of exclusion and that it comes in two flavors, acute vs chronic. In HRS, you will see: increased serum Cr (>.3), normal urine sediment, minimal proteinuria, decreased urine sodium and oliguria (<500 mL urine / day).

  • If patients come in complaining of dyspnea, a good physical exam maneuver is to assess whether they feel more short of breath laying down (which would suggest heart failure) vs sitting up (AKA platypnea and would suggest cirrhosis).

Resident responsibilities:

  • Anytime a patient comes in with hypervolemia, it is important to recognize that there are multiple organs that can cause this, such as liver, heart, or kidney dysfunction. Therefore, remember to think broadly! This is important because with treatment is very different (i.e. aggressive diuresis vs fluid repletion).

  • Important labs to get are BNP, troponin, lactate, BMP for creatinine, CBC, LFTs, and UA. Don’t forget to order an infectious workup as sepsis can worsen hepatorenal pathology by causing systemic vasodilation!!

  • You should also get an EKG, TTE (if the patient has not had one in >1 year), and RUQUS can help further point you towards the heart vs the liver.

  • Most importantly, the patient will need a paracentesis to help establish whether this is primary liver vs cardiac pathology. Remember that the SAAG will be >1.1 in both cardiac vs hepatic ascites; however, the total protein will be <2.5 in cirrhosis ascites and >2.5 in cardiac ascites. 

Further Readings / Learning:

How’d we do?

The following individuals contributed to this topic: Hasan Raza, MD, Sean Tompkins, MD, PhD

Chapter Resources

  • Schuppan D, Afdhal NH. Liver cirrhosis. Lancet. 2008;371(9615):838-851. doi:10.1016/S0140-6736(08)60383-9

  • Wadei HM, Mai ML, Ahsan N, Gonwa TA. Hepatorenal syndrome. Clinical Journal of the American Society of Nephrology. 2006;1(5):1066-1079. doi:10.2215/cjn.01340406  

  • Flamm SL, Brown K, Wadei HM, et al. The current management of hepatorenal syndrome–acute kidney injury in the United States and the potential of Terlipressin. Liver Transplantation. 2021;27(8):1191-1202. doi:10.1002/lt.26072

  • Rangaswami J, Bhalla V, Blair JEA, et al. Cardiorenal Syndrome: Classification, pathophysiology, diagnosis, and treatment strategies: A scientific statement from the American Heart Association. Circulation. 2019;139(16). doi:10.1161/cir.0000000000000664

  • Wong F, Pappas SC, Curry MP, et al. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. New England Journal of Medicine. 2021;384(9):818-828. doi:10.1056/nejmoa2008290

  • Guevara M, Arroyo V. Hepatorenal syndrome. Expert Opin Pharmacother. 2011;12(9):1405-1417. doi:10.1517/14656566.2011.561200

  • Mezale, Dzeina, et al. ‘Non-Alcoholic Steatohepatitis, Liver Cirrhosis and Hepatocellular Carcinoma: The Molecular Pathways’. Liver Cirrhosis - Update and Current Challenges, InTech, 5 July 2017. Crossref, doi:10.5772/intechopen.68771.