Complications
The most common complication of cirrhosis. Treatment involves a no-added-salt diet and diuretics. Evidence suggests that severe dietary sodium restriction may be more harmful than beneficial, and many clinicians advise a no-added-salt diet rather than a low-salt diet.[101] This means excluding additional table salt being added to foods and avoidance of foods with high salt content, such as crisps and some processed meals. This results in a moderate sodium restriction with daily intake of not more than 5 to 6.5 g. First-line choice of diuretic should be spironolactone due to its effects on aldosterone. Furosemide may be added in patients who do not respond. Renal function and electrolytes should be monitored carefully when initiating diuretics and after dose escalation. Non-steroidal anti-inflammatory drugs, ACE inhibitors, and other nephrotoxins should be avoided in patients with ascites.
Every patient with new-onset ascites should undergo a diagnostic paracentesis: cell count with differential, albumin, and total protein should be measured in the ascitic fluid. Ascitic fluid should also be sent for culture and cytology.
Patients with refractory ascites (maximum diuretic doses not sufficient to control ascites or unacceptable adverse effects/complications with diuretic therapy) can be managed with large-volume paracentesis (LVP) and albumin replacement for symptom control. Patients not suitable for liver transplantation should be considered for transjugular intrahepatic portosystemic shunt (TIPS) placement.[103] Meta-analyses indicate that TIPS is more effective than paracentesis for control of refractory ascites, but is associated with a higher incidence of hepatic encephalopathy.[103][104][105][106][107][108][109] Overall mortality does not appear to differ between the two interventions, but TIPS may confer a modest benefit with respect to transplant-free survival.[103][104][105][106][107][108][109] One Cochrane systematic review and network meta-analysis reported that the overall certainty (quality) of evidence was very low, primarily because of unclear or high risk of bias in trials assessing interventions for the treatment of refractory ascites in patients with cirrhosis.[103]
[ 
]
Disease severity at the time of TIPS placement is an important predictive factor for outcomes.[112]
Long-term abdominal drains may be used in the palliative care setting.[113] Prospective randomised controlled trials are warranted.
The use of vaptans (vasopressin V2-receptor antagonists) may have a slight beneficial effect on ascites and hyponatraemia, but they do not reduce mortality, liver complications, or renal failure.[114][115]
Varices are present in 50% of patients with cirrhosis, and variceal bleeding is the most common lethal complication of cirrhosis with an associated mortality of 20% at 6 weeks.[116] Patients with cirrhosis have historically been offered upper gastrointestinal endoscopy for screening of gastro-oesophageal varices at the time of diagnosis, and at 1- to 3-year intervals thereafter.[56] However, guideline recommendations vary regarding screening intervals. The Baveno VII criteria suggest that screening endoscopy could be reserved for a subgroup of patients, based on liver stiffness measurement and platelet count assessment.[54] In particular, patients with compensated cirrhosis, who have a liver stiffness <20 kPa (as measured by transient elastography) and platelet count >150 × 10⁹ cells/L, have a very low risk of having varices requiring treatment and can avoid screening endoscopy.[54] In practice, however, many centres offer baseline endoscopy to all patients with liver cirrhosis.
Prophylaxis of bleeding
Prophylaxis with either non-selective beta-blockers (propranolol, nadolol, or carvedilol) or endoscopic variceal ligation (EVL), which requires several sessions to obliterate varices, should be implemented if high-risk oesophageal varices are present, due to the increased risk of variceal bleeding.[57]
[ ]
High-risk varices include small varices with red signs, medium or large varices irrespective of Child-Pugh classification, or small varices in Child-Pugh C patients.[88] Isolated gastric varices or oesophageal varices extending below the cardia into the gastric fundus should also be considered for non-selective beta-blockers for primary prophylaxis.[54]
Advantages of non-selective beta-blockers include low cost and ease of administration. In addition, once a patient is on non-selective beta-blockers, there is no need for repeat oesophagogastrosduodenoscopy (OGD), and haemodynamic responders to non-selective beta-blockers have a lower incidence of decompensation and death. Disadvantages are that approximately 15% of patients may have absolute or relative contraindications to therapy, and another 15% require dose reduction or discontinuation attributed to common adverse effects (e.g., fatigue, weakness, and shortness of breath) that resolve upon discontinuation, but that may discourage patients and their physicians from using these drugs.
Monitoring haemodynamic response while treating a patient with beta-blockers is associated with a lower risk of variceal bleeding, but large cohort randomised controlled trials are required to confirm these findings.[117]
There is ongoing debate regarding the safety of non-selective beta-blockers in patients with cirrhosis and refractory ascites. The expanded Baveno VI criteria proposed that in patients with refractory ascites and (i) systolic blood pressure <90 mmHg, or (ii) serum creatinine >133 micromoles/L (>1.5 mg/dL), or (iii) hyponatraemia <130 millimoles/L, the beta-blocker should be reduced in dose or even temporarily discontinued.[87] However, there is evidence to suggest that the risk of harm may not be significant.[118][119][120][121]
EVL is an alternative to non-selective beta-blockers. It is a local therapy that involves placing elastic bands around oesophageal varices until they are obliterated. EVL can theoretically be performed in the same session as screening endoscopy with hardly any contraindications. Disadvantages of EVL include the risks associated with sedation, plus the risk of causing dysphagia, oesophageal ulceration, strictures, and bleeding. Adverse effects associated with EVL may be severe, with reports of deaths resulting from EVL-induced bleeding ulcers. EVL is unable to prevent complications other than variceal haemorrhage. Surveillance endoscopies are necessary after variceal eradication, at least annually, to detect variceal recurrence.[122] Child-Pugh class C, ascites, or low prothrombin index are all indicators for high risk of early bleeding following EVL.[123]
The choice of whether to use non-selective beta-blockers or EVL should be based on local resources and expertise, patient preference and characteristics, contraindications, and adverse events.[87] One meta-analysis that included 1023 patients compared prophylactic EVL with beta-blockers and found that there was no difference between the treatments with regard to gastrointestinal haemorrhage, all-cause mortality, or haemorrhage-related mortality. While there was a decrease in variceal haemorrhage with EVL compared with beta-blockers (relative risk [RR] 0.72, 95% CI 0.4 to 0.96), variceal haemorrhage was not significantly different between the two groups when only high-quality trials were considered (RR 0.84, 95% CI 0.60 to 1.17).[124] Subjective factors influence the physician's choice in selecting non-selective beta-blockers versus EVL, as illustrated in an interview-based study in which gastroenterologists who spent at least half their time performing endoscopy were more likely to choose EVL, whereas physicians who had a less procedural-based practice were more likely to choose non-selective beta-blockers.[125]
Transjugular intrahepatic portosystemic shunts (TIPS)
TIPS may be used as a secondary treatment option for oesophageal varices in cirrhosis but is not recommended for primary prophylaxis of variceal haemorrhage.[2][126] Evidence obtained from trials of prophylactic surgical shunt therapy show a significantly higher rate of encephalopathy and a tendency for a higher mortality in patients randomised to shunt surgery.[127]
Management of acute variceal haemorrhage
An episode of acute variceal haemorrhage should be managed as a medical emergency with intravascular volume support, blood transfusion (with the aim of keeping the haemoglobin around 70-80 g/L [7-8 g/dL]), and a combination of endoscopic and pharmacological therapy.[131] Terlipressin (a vasopressin analogue), or somatostatin (or its analogue octreotide) should be initiated as soon as a variceal bleed is suspected and continued for 2-5 days if it is confirmed.[132] Upper gastrointestinal endoscopy should be performed within 24 hours to confirm the diagnosis and allow treatment with EVL or sclerotherapy.[133]
Short-term (up to 7 days) antibiotic prophylaxis should be instituted in all patients following a gastrointestinal haemorrhage (regardless of the presence of ascites) as this has been shown to decrease the rate of bacterial infections and increase survival.[134]
[ ]
Ceftriaxone is the first choice in patients with decompensated cirrhosis, in those already on fluoroquinolone prophylaxis, and in hospital settings with high prevalence of fluoroquinolone-resistant bacterial infections. Oral fluoroquinolones should be used in the remaining patients.[135][136]
Life-threatening bleeding may be controlled with a Sengstaken-Blakemore tube or a Danis stent until haemostasis can be achieved endoscopically, or with TIPS, with or without embolisation.[137]
It is recommended that patients hospitalised with cirrhosis receive formal dietician assessment, and steps should be taken to minimise the fasting period prior to procedures (e.g., by giving them a pre-bedtime snack or early-morning snack if the procedure will be in the late afternoon).[138] Parenteral supplementation may be required for those who cannot meet their nutritional intake needs orally. Recommended protein intake for adults with cirrhosis is 1.2 to 1.5 g/kg (ideal body weight) per day, and 1.2 to 2 g/kg (ideal body weight) per day if critically ill.
Patients with cirrhosis, especially those with viral hepatitis (type B and C), alcohol-related liver disease, and haemochromatosis, are at high risk of developing hepatocellular carcinoma and should therefore undergo surveillance with ultrasound, with or without alpha-fetoprotein, every 6 months.[170] Alpha-fetoprotein cannot be recommended as a single test because it is neither sensitive nor specific for hepatocellular carcinoma.
There are several different treatment options for hepatocellular carcinoma depending on its stage and the degree of liver dysfunction. These include liver transplantation, surgical resection, radiofrequency ablation, microwave ablation, and transarterial chemoembolisation. Advanced hepatocellular carcinoma may be treated using sorafenib as palliative chemotherapy.
The Barcelona Clinic Liver Center (BCLC) classification for staging and treatment of hepatocellular carcinoma is endorsed by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver.[62][170] The BCLC staging system correlates each of its stages with treatment modalities and estimates the life expectancy based on prior studies.[170]
The haemostatic balance in liver disease is fragile, and the risk of bleeding/thrombosis is poorly predicted by routinely used diagnostic tests, such as international normalised ratio (INR).
Patients with advanced liver disease often have thrombocytopenia due to hypersplenism. There is a concurrent reduction in synthesis of clotting factors, leading to elevations in INR. Portal hypertension or hyperfibrinolysis may give rise to bleeding. Lusutrombopag and avatrombopag are approved for thrombocytopenia in adults with chronic liver disease undergoing invasive procedures.[195]
Anticoagulation is frequently withheld from hospitalised patients with cirrhosis because of concerns over laboratory parameters. Thromboelastography may ultimately have a role in the evaluation of clotting in patients with cirrhosis, but validated target levels are lacking.[196][197][198] It has been increasingly recognised that patients with cirrhosis are at significant risk of venous thromboembolism (VTE), with typical incidence rates of 0.5% to 1.9%, but in some studies considerably higher.[46][199] In hospitalised patients with cirrhosis who otherwise meet standard guidelines for the use of VTE prophylaxis, standard anticoagulation prophylaxis should be used.[46]
The American Gastroenterological Association has published guidelines with recommendations for achieving haemostasis, as well as the prevention and treatment of thrombosis, in patients with cirrhosis.[46]
A peritoneal fluid absolute neutrophil count >250 cells/mm³ is the accepted criterion for the diagnosis for spontaneous bacterial peritonitis.[88]
Treatment is with intravenous antibiotics, such as cefotaxime or a fluoroquinolone, and intravenous human albumin solution. Albumin has been shown to reduce mortality in patients with cirrhosis with spontaneous bacterial peritonitis.[139][140]
All patients who have survived an episode of spontaneous bacterial peritonitis require lifelong secondary antibiotic prophylaxis.[192]
Patients with ascites and an ascitic fluid total protein level of ≤10 g/L are at high risk of developing spontaneous bacterial peritonitis and should be considered for primary antibiotic prophylaxis.[88][141][142] There appears to be an increased risk of spontaneous bacterial peritonitis with the use of proton-pump inhibitors.[143] High-quality evidence for this intervention is lacking and further trials are needed to establish whether antibiotic prophylaxis for people with cirrhosis is beneficial.[144]
Occurs in approximately 5% to 10% of patients with cirrhosis, usually in patients with ascites.[145]
Hepatic hydrothorax may cause dyspnoea.
Management is similar to that of ascites. In some patients, long-term indwelling catheters are required for symptomatic management.[146][147] Patients with hepatic hydrothorax should be evaluated for liver transplantation.[148]
Approximately 11% of patients with cirrhosis have hepatic encephalopathy at the time of cirrhosis diagnosis.[149] Around 30% to 40% of patients with cirrhosis have an episode of hepatic encephalopathy during their illness, and there is a 30% to 40% chance of recurrence in the following year.[150]
Hepatic encephalopathy is characterised by changes in consciousness, behaviour, and personality, with disorientation, drowsiness, forgetfulness, confusion, agitation, and eventual coma. Slurred speech, asterixis (liver flap), increased muscle tone, and extensor plantar reflexes may be present.
Precipitating factors include gastrointestinal haemorrhage, constipation, diarrhoea and vomiting, hypoglycaemia, and electrolyte imbalance; drugs (diuretics, sedatives) and medical procedures (paracentesis, transjugular intrahepatic portosystemic shunt [TIPS]); infection, anaemia, hypoxia, and hypotension.
Serum ammonia levels are usually elevated, but there is poor correlation between ammonia level and the degree of encephalopathy.
There appears to be an increased risk of hepatic encephalopathy with the use of proton-pump inhibitors.[151][152]
Treatment involves identification and correction of reversible precipitating factors and lactulose, used alone or in combination with antibiotics such as rifaximin.[153][154][155][156][157][158][193]
Dietary protein restriction is not recommended.[159]
HRS-AKI (formerly known as type-1 hepatorenal syndrome) can be diagnosed if patients meet the following criteria, as defined by the International Club of Ascites: cirrhosis with ascites; diagnosis of AKI according to ICA-AKI criteria (i.e., increase in serum creatinine ≥26.4 micromoles/L [≥0.3 mg/dL] within 48 hours, or a percentage increase in serum creatinine ≥50% from baseline which is known, or presumed, to have occurred within the previous 7 days; [the American Gastroenterological Association (AGA) also include a reduction of urine output to below 0.5 mL/kg/h for >6 hours]); no response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin; absence of shock; no current or recent use of nephrotoxic drugs (non-steroidal anti-inflammatory drugs, aminoglycosides, or iodinated contrast media); no macroscopic signs of structural kidney injury (structural kidney injury is indicated by proteinuria [>500 mg/day], microhaematuria [>50 red blood cells per high-power field], and/or abnormal renal ultrasonography).[89][90]
European Association for the Study of the Liver (EASL) guidelines recommend using an adapted staging system for AKI that splits AKI stage 1 into stage 1A and 1B according to a serum creatinine value of <133 micromoles/L (<1.5 mg/dL) or ≥133 micromoles/L (≥1.5 mg/dL), respectively.[88]
Measures can be taken to prevent HRS-AKI from developing in patients with cirrhosis, and include: advising patients to avoid alcohol; monitoring serum creatinine levels and electrolytes when diuretics are given and avoiding excessive diuretics; avoiding large-volume paracentesis without albumin replacement; giving prophylactic antibiotics when infection is strongly suspected (investigations should include diagnostic paracentesis to evaluate for spontaneous bacterial peritonitis); and avoiding use of non-selective beta-blockers and nephrotoxic drugs (e.g., ACE inhibitors, angiotensin II receptors blockers, and non-steroidal anti-inflammatory drugs [NSAIDs]).[90]
Once diagnosed, treatment of the precipitating cause should be initiated and any non-selective beta-blockers, diuretics and NSAIDS held or stopped. Fluid losses should be replaced and fluid status monitored.[90]
Vasoconstrictors and albumin are recommended in all patients and should be expeditiously used. Terlipressin plus albumin should be considered as the first-line therapeutic option.[132] Noradrenaline (norepinephrine) can be an alternative to terlipressin. However, there are several limitations associated with its use. Midodrine plus octreotide can be an option when terlipressin or noradrenaline are unavailable, but its efficacy is much lower than that of terlipressin.[88][194] In one phase 3 trial to confirm the efficacy and safety of terlipressin plus albumin in adults with HRS-AKI, terlipressin was more effective than placebo in improving renal function, but was associated with serious adverse events, including respiratory failure, and cases of sepsis or septic shock.[161]
Results from portal hypertension and occurs in at least 5% of patients awaiting liver transplantation.[163] Symptoms include dyspnoea and platypnoea. The diagnosis includes the finding of hypoxaemia with increased alveolar-arterial gradient, orthodeoxia, and the determination of intrapulmonary vascular dilatation on contrast-enhanced echocardiography.
The presence of hepatopulmonary syndrome should prompt immediate evaluation for liver transplantation.
The condition usually resolves following liver transplantation.[164]
This complication is diagnosed when findings of unexplained pulmonary hypertension are present in association with portal hypertension.
Unlike hepatopulmonary syndrome, this condition may not completely resolve following liver transplantation. Patients with severe pulmonary hypertension that does not improve with the use of vasodilators such as epoprostenol, bosentan, iloprost, or sildenafil are not candidates for liver transplantation in view of the high risk of death associated with the procedure.
In one randomised controlled trial, macitentan, an endothelin-receptor antagonist, significantly reduced pulmonary vascular resistance in patients with portopulmonary hypertension compared with placebo.[165]
Acute-on-chronic liver failure (ACLF) is a severe form of acutely decompensated cirrhosis with organ failure and a high risk of short-term mortality.[166] It is a heterogeneous syndrome; affected patients have features of hepatic failure (coagulopathy, elevated bilirubin) and may also have extrahepatic organ failure (kidney, lung, brain, or circulation). ACLF may be precipitated by alcohol use, viral hepatitis, drug-induced liver injury, surgery, ischaemia, or infection. It is a potentially reversible condition that may occur in people with chronic liver disease.
Treatment includes resuscitation, treatment of the precipitating factor, support of failing organs, and assessment for and early treatment of infection. Patients should be cared for in the intensive care unit. Some patients may benefit from early liver transplantation.[167]
Treatment of shock in ACLF can be challenging. Society of Critical Care Medicine guidelines recommend using albumin as a resuscitation fluid over other fluids, particularly when serum albumin is below 3 mg/dL.[168] Guidelines recommend aiming for a mean arterial pressure of 65 mmHg alongside invasive haemodynamic monitoring.[168][169] In patients with ACLF and hypotension, human albumin or crystalloids should be used for initial fluid therapy.[166] If vasopressors are required, noradrenaline (norepinephrine) is more effective than dopamine in reversing hypotension. The European Association for the Study of the Liver (EASL) recommends against the use of dopamine in patients with ACLF.[166] Low-dose vasopressin can be added to noradrenaline in patients with ACLF who remain hypotensive despite fluid resuscitation. The American Association for the Study of Liver Diseases (AASLD) recommends noradrenaline as the first-line agent and vasopressin as the second-line agent for managing patients with hypotension.[169] The possible mortality benefit with the addition of vasopressin must be weighed against increased risk of digital ischaemia. As well as addressing the treatment of shock, the guidelines also provide recommendations for managing endocrine, haematological, pulmonary, and renal features of ACLF in the intensive care unit setting.[168][169]
Cirrhosis is associated with an oestrogenic/androgenic imbalance with reduced circulating levels of testosterone and a relative increase in oestrogen. This leads to hypogonadism and feminisation in men. Hypogonadism is characterised by testicular atrophy, impotence, and loss of libido, while gynaecomastia and a female pattern of hair distribution are features of feminisation. Testicular atrophy and reduced libido are most commonly seen in patients with underlying alcohol-related liver disease and haemochromatosis.
In women, this endocrine imbalance may cause amenorrhoea, infertility, acne vulgaris, and the development of benign breast cysts.
This is the term given to the combination of osteoporosis and osteomalacia associated with chronic liver disease. Hepatic osteodystrophy most commonly occurs with underlying cholestatic disease (primary biliary cholangitis and primary sclerosing cholangitis), but can occur with any chronic liver disease. Osteoporosis results from reduced bone mineralisation and formation secondary to decreased activity of osteoblasts. This leads to pathological fractures, particularly of the vertebrae; back pain; and kyphosis. Osteomalacia is less common and results from reduced bone mineralisation. Its main symptom is bone pain. Vitamin D deficiency is a contributory factor in the development of hepatic osteodystrophy.
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