Retrospective analyses indicate enhanced survival in cirrhotic patients compared with two decades ago. Whilst this may in part reflect earlier diagnosis of cirrhosis and thus an apparent rather than a real change in outlook, management of the complications of cirrhosis has undoubtedly improved, and for individual patients this clearly confers survival benefit. This talk will concentrate on such areas, notably surveillance for hepatocellular cancer, the management of hepato-renal syndrome, transhepatic portal-systemic shunting for bleeding, and selection for transplantation.
Surveillance for hepatocellular cancer (HCC)
Cirrhosis is present in ~80% of the ~500,000 cases of HCC diagnosed yearly. In Europe Hepatitis C and alcohol are the most common backgrounds, followed by HBV. The annual incidence of HCC in cirrhosis has been estimated as ~4%. Surveillance for HCC is therefore an attractive proposition, although prospective trials have not confirmed survival benefit. However, as small HCCs can be cured - by local ablation, by resection, or by transplantation, individual benefit is likely to be achievable.
Whom to screen. Most centres only screen male patients with cirrhosis. The incidence in females, and patients with PBC, Wilson's and auto-immune hepatitis is much lower than the annual 4% noted above. If a patient is not suitable for a potentially curative procedure they should not be enrolled in a surveillance programme.
Screening procedures. Only two are sufficiently robust and available - Serum alphafoetoprotein estimation and ultrasound. AFP is imperfect - with a sensitivity of 40-60%, and a specificity of 75-90%. Ultrasound sensitivity is higher (70%) and specificity better (93%). Without prospective evidence, recommendations (EASL) are for 6-monthly US and AFP estimations. An elevated AFP without ultrasound abnormalities will trigger a second imaging procedure or a recall ultrasound. The US evidence is based on the concept that growth from undetectable to 2 cm takes 4-12 months.
Specific recommendations are
<1cm - (if AFP normal) repeat (after 2-3 months) until >1cm Rationale - at this size <50% detected lesions are HCC and confirming the diagnosis at that size is difficult
1-2cm - Biopsy if AFP normal
2cm + - image by another technique - at this size if 2 techniques demonstrate an arterial hypervascularized lesion, HCC diagnosis can be accepted.
Treatment Both surgical resection and local ablation (percutaneous ethanol) can be curative if tumours are small (<3-4 cm for ethanol injection). However, it is important to recall that HCC in a cirrhotic liver arises in a background of dysplasia that will persist in the liver after curative resection or local treatment. Transplantation for well-selected patients (single tumours <5cm or 3 tumours <3 cm) can have comparable survivals to non-malignant HCC; after successful transplantation the recurrence rate at 5-years is <30% cf 60-70% after local treatment.
Management of hepato-renal syndrome
Hepatorenal failure - the functional failure of anatomically normal kidneys in the setting of cirrhosis - has a notoriously poor prognosis, but recent changes in understanding and management have improved outcomes strikingly. The classical patient has cirrhosis, hyponatraemia, and ascites, and may have been over-diuresed.
Pathophysiology The major concept is that renal vasoconstriction underlies the diminished renal function, arising as a consequence of changes in systemic and portal haemodynamics. In simple terms, vasodilatation of cirrhosis associated with splanchic pooling of blood, and consequent vascular underfilling, initiates (in the presence of portal hypertension) renal vasoconstrictive influences (renin, angiotensin, endothelin). A major boost for this theory has come from the practical demonstration that vasoconstrictors acting on the splanchnic and systemic circulation can reverse these changes.
Definitions Type I HRS describes an acute change (seen for example in the setting of an episode of spontaneous bacterial peritonitis complicating chronic ascites) - with an arbitrary definition of a two-fold increase in serum creatinine to >220 umol/l over 2 weeks. Type II is a slower change resulting in a moderate stable renal failure (generally creatinine 1-2 x upper limit of normal). The differential diagnosis from volume depletion and the value of fluid challenges, volume expansion and cessation of diuretics have been widely emphasised.
Prevention
In two clear clinical circumstances, there is good controlled evidence of successful preventative treatment - a) the use of supplemental albumin (1.5 g/kg at diagnosis, 1g/kg 24h later), in addition to antibiotic treatment, in spontaneous bacterial peritonitis, and b) the use of pentoxyfylline (400 mg tds) in the treatment of alcoholic hepatitis.
Treatment Whilst liver transplantation provides definitive treatment for HRS, poor renal function increases the risk of the procedure. A variety of approaches have been used - molecular adsorption recirculation (MARS), prostaglandins (as renal vasodilators), transhepatic portal systemic shunts (which reverse the portal hypertension and indirectly may improve the renal circulation) and most convincingly vasopressin analogues. These (initially ornipressin but now terlipressin) are potent splanchnic vasoconstrictors.
Terlipressin given over days to 2 weeks (0.5 to 2 mg/6hrly), when given together with albumin, returns creatinine to the normal range in over 50% of patients with HRS, and generally the improvement is maintained after the cessation of treatment. Whilst there are no comparative trials comparing terlipressin with TIPPS in the setting of HRS, the vasoconstrictor appears superior on cost and availability.
The current role of TIPSS
The technically impressive procedure of TIPPS is limited in general usage by availability of skilled personell and complications (eg stenosis). More expensive shunts may improve the technical outcome but the complications of encephalopathy, or deterioration of function in Child's C cirrhotics remain. In current practice the use of TIPPS is a) as 'rescue' therapy in variceal haemorrhage uncontrolled endoscopically b) in chronic cirrhotic ascites and c) Budd-Chiari syndrome. In these it may act as a bridge to transplantation.
Changing indications for transplantation
Indications for transplantation have changed reflecting changes in selection, epidemiology and treatment. In many countries, the store of stable cholestatic patients (PBC) has been treated. The ability to control HBV predictably by use of HBIg and lamivudine has dramatically improved outcome in that group. The hepatitis C epidemic has rendered this the major indication for TP in many countries, although outcomes remain poor due to early recurrence and accelerated fibrosis in grafted organs. With early detection of small tumours, HCC is increasingly often the indication. Alcoholics are now more likely to be accepted, although most centres prefer to wait for 6 months abstinence- not least because of the regeneration and improvement in liver function that can occur in the reformed alcoholic. A shortage of organ donors remains the major factor constraining transplant programmes, with some increase in supply from more marginal organs, domino transplants, split livers and live related programmes. |