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Dr. Mohamed AlshekhaniProfessor in Medicine.

MBChB-CABM-FRCP-EBGH.2015

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Overview:• Cardiac hepatopathy: any liver damage caused by cardiac disorders

in the absence of other possible causes of liver damage.• Cardiac hepatopathy includes congestive hepatopathy (CH) & acute

cardiogenic liver injury (ACLI). • CH is caused by passive venous congestion of the liver that

generally occurs in the setting of chronic cardiac conditions such as chronic HF, constrictive pericarditis, tricuspid regurgitation, or right-sided heart failure (HF) of any cause,

• ACLI is most commonly associated with acute cardiocirculatory failure resulting from acute myocardial infarction, acute decompensated HF, or myocarditis.

• Acute & chronic HF may be complicated with liver damage, which has significant implications on the patient management&underlying heart disease outcomes.

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Overview:• Histologically:• CH is characterized by sinusoidal dilation, replacement of

hepatocytes with red blood cells extravasating from the sinusoids, & necrosis/apoptosis of zone 3 of the Rappaport acinus& it could progress to cirrhosis in advanced cases.

• In ACLI, massive necrosis of zone 3 is the main histological finding.

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Overview:• Primary lab findings of:• CH: elevated serum cholestasis markers including bilirubin, alkaline

phosphatase, γ-glutamyl-transpeptidase.• ACLI: striking elevation in transaminase & lactate dehydrogenase. • Both CH &ACLI have a prognostic value for identifying CV events &

mortality& have some special implications in the management of patients undergoing ventricular assist device implantation or cardiac transplantation.

• There is no specific treatment for CH or ACLI other than treatment of the underlying cardiac disorder.

INTRODUCTION:• HF, a systemic clinical syndrome with typical symptoms/signs

(dyspnea, leg swelling, PND&orthopnea) result from any structural or functional impairment of ventricular filling or ejection

• . HF is a major health problem with significant personal&public implications.

• 5.1 million people have HF, 50% die within 5 years of diagnosis, despite improved survival during the recent years with some advances in medical / device therapies.

• HF may result from congenital or acquired disorders of the pericardium, myocardium, endocardium,heart valves, great vessels, heart rhythm, or conduction or from certain metabolic abnormalities.

• Disorders of the left ventricular myocardium impairing the ability of the left ventricle (LV) to fill with or eject blood is the underlying cause in the most.

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INTRODUCTION:• HFpEF>50% is predominantly a disease affecting older women with

hypertension with prevalence of 50% with morbidity&mortality rates comparable with those of HFrEF<50%.

• In HF, the heart cannot deliver oxygen at a rate proportionate to the demands of the metabolizing tissues that may result in damage to other organ systems such as kidney, BM, or liver.

• A spectrum of liver damages from mild (LFT) abnormalities to cardiac cirrhosis has been reported in both chronic & acute HF.

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Pathophysio of liver damage in HF:• In primary pathophysio is either:• Chronic passive venous congestion causing congestive hepatopathy• Or low CO & arterial hypoperfusion results in “ (ACLI)” ,Synonomes;

Ischemic hepatitis, shock liver, or hypoxic hepatopathy. • CH generally occurs in chronic cardiac conditions increasing

systemic venous pressure as chronic HF, constrictive pericarditis, MS, TR, cor pulmonale, severe PAHT, long-standing Fontan procedure, or right-sided HF of any cause.

• Acute cardiogenic liver injury, is most commonly associated with acute cardiocirculatory failure from AMI, ADHF, myocarditis, or massive PE.

• Passive congestion secondary to right-sided HF& reduced arterial perfusion&oxygenation due to left-sided HF often coexist& potentiate the deleterious effects of each other on the liver.

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Pathophysio of liver damage in HF:• The liver is enlarged, tender, firm in CH. • The main histological finding in a congestive liver is hemorrhage /

necrosis of zone 3 of the Rappaport acinus with normal or mildly steatotic areas in zones 1 & 2.

• Because obesity, hyperlipidemia,diabetes are common risk factors for both HF&hepatosteatosis, non-alcoholic hepatosteatosis is frequently observed in CH patients.

• The changes in zone 3,largely depend on the transmission of elevated systemic venous pressure to hepatic sinusoids through hepatic vessels that result in sinusoidal dilation, replacement of hepatocytes with red blood cells extravasating from the sinusoids, & centrilobular tissue destruction.

• Apoptosis is the major process of cell death in chronic HF, whereas necrotic cell death is prominent in acute HF.

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Pathophysio of liver damage in HF:• In CH, increased venous pressure also promotes ascites formation,

which is present in up to 60% of cardiac hepatopathy patients, bile duct damage & thrombi formation in sinusoids, hepatic venules, portal tracts.

• If congestion remains for a longer duration, these changes are followed by the deposition of collagen to forming fibrous septa and bridges between adjacent central veins ultimately cardiac cirrhosis.

• To date, cardiac cirrhosis, in general, is rare, but it is still important in special patient groups such as Fontan survivors, overlooked constrictive pericarditis&untreated severe TR.

• In contrast to primary liver disease-related cirrhosis, cardiac cirrhosis shows a reverse lobulated pattern, in which damage is more prominent in zone 3 than in zone 1.

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Pathophysio of liver damage in HF:• Another distinct feature of cardiac cirrhosis is the presence of a

matched distribution pattern between liver fibrosis& fibrous obliteration of hepatic& portal veins caused by organized thrombi. Through fibroblast activating effect of focal thrombi.

• Vascular congestion caused by HF can induce a transient increase in liver stiffness assessed by elastography, which can mislead the diagnosis of liver cirrhosis.

• In HF patients, the diagnosis of cardiac cirrhosis should be based on clinical, biochemical&radiographic findings.

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Pathophysio of liver damage in HF:• Because the liver has a high metabolic activity / perfusion rate,

acute circulatory changes such as cardiogenic shock or ADHF may result in ACLI when the liver’s compensatory mechanism of increasing oxygen extraction from the blood (up to 95%) is being insufficient in the setting of persistent circulatory failure.

• Hepatic blood flow declines by 10% for every 10 mmHg drop in arterial pressure; but with this excellent compensatory mechanism, previously healthy individuals with shock do not appear to frequently develop liver damage frequently &all ischemic hepatitis patients had a severe underlying cardiac disorder with passive congestion of the liver,suggesing that a baseline hepatic congestion is required to predispose the liver to damage induced by a hypotensive event.

• Histologically, ACLI is characterized by necrosis of pericentral zone 3 hepatocytes, which receive poorly oxygenated blood compared to periportal zone 1 & 2. 11

Clinical implications:• Congestive hepatopathy is generally asymptomatic, but a mild

discomfort in RUQ caused by liver capsule stretching, early satiety, nausea& anorexia is reported by some.

• Jaundice (1.2% of jaundice due to HF ), tender hepatomegaly, HJ reflux, ascites, pulsatile liver are the main findings on PE.

• HJR: sustained rise of >3 cm in the jugular venous pressure elucidated by the application of firm consistent pressure to the right upper quadrant,a very useful maneuver for predicting HF.

• Pulsatile liver is generally caused by TR, TS, constrictive pericarditis, restrictive cardiomyopathy, or pulmonary hypertension.

• Splenomegaly is present in a minority of chronic HF, but esophageal varices are rare because of a normal hepatic venous pressure gradient in majority.

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Clinical implications:• Acute cardiogenic liver injury is generally asymptomatic, but

nausea, vomiting, weakness, right upper quadrant pain,apathy may be present after a latent period of 2–24 h after the acute event.

• In minority of cases, mental confusion,jaundice, flapping tremor, or hepatic coma might develop;but mental confusion/coma generally represent cerebral hypoxia rather than hepatic encephalopathy.

• Fulminant hepatic failure reported in rare cases of HF ,4.4% had ischemic hepatitis.

• Only 31% had knowledge regarding their cardiac disease before presentation,but a cardiopulmonary precipitant of hepatic ischemia was identified in 69%&hepatic encephalopathy was found to be associated with short-term mortality, but long-term prognosis was largely determined by the underlying cardiac disorder.

• In another study of ALF, cardiogenic shock found in 13 with mortality of 54% &only cardiac index was different between survivors &non-survivors. 13

Clinical implications:• In some patients with ALF, underlying cardiogenic cause may not be

so obvious at first. • An abnormal ECG associated with cardiac murmurs should warrant

an Echo for diagnosis in patients with acute liver failure of unknown etiology.

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Acute Ischemic Hepatitis:• Recently, the prodrome of acute ischemic hepatitis (shock liver) has

been reported in patients with cardiogenic shock ,who have acute DIC along with symmetric peripheral gangrene or purpura fulminans.

• Combined acral & nonacral skin necrosis (i.e.purpura fulminans) developes.

• Before the onset of ischemic limb necrosis, acute ischemic hepatitis (peak ALT&acute, severe thrombocytopenia.

• DIC shown by an elevated INR, hypofibrinogenemia (fibrinogen nadir,, elevated APTT& greatly elevated fibrin- specific markers.

• At the onset of necrosis, the protein C activity markedly reduced.

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Acute Ischemic Hepatitis:• Protein C severely reduced& irreversible tissue necrosis evident. • Marked thrombin generation &fibrin formation continued, as

shown by greatly elevated thrombin–antithrombin complexes / fibrin d-dimer levels, respectively .

• Treatment with unfractionated heparin to a therapeutic level (according to anti–factor Xa levels) was accompanied by APTT levels of >150 seconds

• Preceding shock liver is a common finding that is observed in 90% of critically ill patients with DIC in whom acral ischemic necrosis develops.

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Acute Ischemic Hepatitis:• The onset of ischemic limb necrosis usually begins 2 -5 days after

the initial elevation in liver enzymes, a similar time for skin necrosis after the initiation of warfarin therapy,presumably reflects the time required for the development of critically low levels of protein C when its synthesis is impaired by acute liver dysfunction or warfarin.

• Some implicate hypotension requiring vasopressors (e.g. dopamine, noradrenaline,or phenylephrine5) in the pathogenesis of symmetric peripheral gangrene.

• In parallel with the role of DVT in predisposing the patient to warfarin-associated microthrombosis in the same limb with large-DVT, it seems plausible that hypotension& vasopressors, by reducing blood flow into the distal extremities, could predispose the patient with DIC to acral microthrombosis.

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Lab implications:• In CH, primary laboratory findings are elevated serum cholestasis

markers including bilirubin,SAP),GGT. • ALT&AST generally show mild elevations up to 2-3 times the normal • A mild decrease in albumin (in 25%) &a slight increase in

prothrombin time are also frequent in CH.• Increase in liver function tests are more strongly correlated with

decreased cardiac index, increased filling pressures& severe TR.• Elevated GGT 43% in men,48% in women ,total bilirubin 17% in men

, 8% in women. • Both GGT & TSB found to be associated with disease severity, but

only GGT is independently associated with adverse outcomes. • TSB is above the upper limit of normal in 13%. • After adjustment for other variables, only TSB was independently

associated with morbidity & mortality.• 21

Lab implications:• Abnormal LFTs are markedly associated with mortality, but AST/ TSB

show the highest association. • AP &GGT are independent predictors of death from any cause. • TSB, AP,GGT independently correlate with functional class and

clinical signs of HF including jugular venous distention, TR, peripheral edema.

• TSB was independent marker for right ventricular failure & LVAD implantation&it is a component of risk models for adverse outcomes after LVAD implantation or cardiac transplantation

• Hypoalbuminemia, mainly caused by HF-associated systemic inflammation, is another prognostic marker in acute & chronic HF

• Hypoalbuminemia has a prognostic value in LVAD& is a component of risk models.

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Lab implications:• The ascites associated with chronic HF also has distinct features that

may aid in making the differential diagnosis. • Cardiac ascites has high protein content (usually≥2.5g/dL) and high

serum ascites albumin gradient (>1.1g/dL) due to preserved synthetic function of the liver.

• Red blood cell counts &LDH are also higher in cardiac ascites than in cirrhotic ascites of other causes due to the extravasation of red blood cells into the ascites with resultant lysis.

• In the differential diagnosis, another useful marker is serum or ascites NT-proBNP&both serum &ascites NT-proBNP have high sensitivity / specificity in predicting HF as the cause of ascites.

• Both ACC &ESC HFGuidelines recommend the inclusion of LFTs in the diagnostic workup of all patients presenting with HF.

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Lab implications:• The typical laboratory finding of ACLI is the presence of a striking

elevation in transaminase &LDH (generally to 10-20 times the normal values, even up to 2000-fold).

• Transaminases&LDH reach their peak 1-3 days after the acute event &return to normal limits within 7-10 days if the patient’s hemodynamics recover.

• In ACLI, an early& rapid increase of LDH in parallel with transaminases, a ratio of ALT to LDH <1.5&decrease in ALT by > 50% within 72 h are characteristic findings that can be useful in the differential diagnosis of acute viral, alcoholic, or drug-induced hepatitis .

• Other lab findings are mild elevations of TSB, AP &PT.• Aabnormal transaminases, low albumin& elevated TSB have a

prognostic value for mortality.

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Management:• There is no specific treatment of CH other than the treatment of the

underlying cardiac disease. • In symptomatic HFrEF patients, diuretics are recommended to

reduce fluid retention&improve symptoms.• Advanced liver dysfunction may have a negative impact on renal

function (hepato-renal syndrome) by way of splanchnic vasodilatation resulting in arterial underfilling&renal vasoconstriction

• In chronic HF, liver congestion may directly contribute to impaired natriuresis.

• Liver congestion, ascites,jaundice may improve with diuretics therapy, but in refractory cases, combination therapy with diuretics paracentesis, ultrafiltration, or peritoneal dialysis may be needed.

• Paracentesis results in a reduction of elevated intraabdominal pressure with corresponding improvement in renal function.

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Management:• ACEI or ARBs in ACE inhibitor intolerant & beta blockers are

recommended in all symptomatic HFrEF, unless contraindicated to reduce morbidity and mortality

• Low-dose mineralocorticoid receptor antagonists (MRAs) are also recommended in symptomatic HFrEF patients with an estimated glomerular filtration rate>30 mL/min/1.73 m2&potassium<5.0 mEq/L to reduce morbidity / mortality.

• In HF patients, MRAs are used in low doses (spironolactone up to 50 mg/day); however, in cirrhosis, natriuretic doses of MRAs (spironolactone up to 400 mg) are recommended as the main therapy to produce a negative sodium balance.

• In suitable refractory HF patients’ cardiac resynchronization therapy, LVAD, or cardiac transplantation are recommended.

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Management:• Cardiac transplantation/ LVAD implantation can improve abnormal

LFTs, but if there is a strong suspicion of advanced liver disease, cirrhosis must be ruled out before the cardiac transplantation or combined liver-heart transplantation is performed in suitable cases.

• In HFpEF, no treatment has shown reduction in morbidity/mortality• Diuretics; controlling systolic/diastolic HT, particularly with ACEI or

ARBs; coronary revascularization; & AF management are recommended in suitable HFpEF patients to relieve symptoms.

• In ACLI, restoration of CO&hemodynamics is the primary goal. • Ventilator support, inotropes/vasopressors, cor recanalization,

mechanical circulatory support should be used in suitable patients.• LFTs should be monitored for recovery. • Seralaxin (recombinant human relaxin-2)improved LFTs in acute HF,

which is consistent with more effective prevention of organ damage 27

Cardiac hepatopathy&cardiovascular drugs:

• The liver, metabolizes many cardiovascular drugs in contrast to the kidney

• Although there are no rules for the modification of drug dosage in the cases of liver dysfunction,because none of the LFT abnormalities sufficiently correlate with the degree of alterations in hepatic drug metabolism ,but it is suggested that individual pharmacokinetic profile of the drug should be considered for the modification of drug dosage.

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Thanks for attention